Pharmaceutical salts, physical forms, and compositions of pyrrolopyrimidine kinase inhibitors, and methods of making same

ABSTRACT

Provided are methods of making certain pyrrolopyrimidine derivatives, which are useful in the treatment of proliferation disorders and other diseases related to the dysregulation of kinase (such as, but not limited to, EGFR (including HER), Alk, PDGFR, BLK, BMX/ETK, BTK, FLT3 (D835Y), ITK, JAK1, JAK2, JAK3, TEC and TXK) and/or the respective pathways, salts, polymorphs, and amorphous forms of said compounds, synthetic intermediates for preparing said compounds, and pharmaceutical compositions comprising said compounds and methods for making such compositions.

TECHNICAL FIELD

Described herein are methods for the preparation of certain pyrrolopyrimidine compounds that are useful for the treatment of proliferation disorders and other diseases related to the dysregulation of kinase (such as, but not limited to, EGFR (including HER), Alk, PDGFR, BLK, BMX/ETK, BTK, FLT3(D835Y), ITK, JAK1, JAK2, JAK3, TEC, and TXK) and/or the respective pathways. Also described herein are certain salt forms and physical forms of said pyrrolopyrimidine compounds, stabilized pharmaceutical compositions comprising said pyrrolopyrimidine compounds and processes for preparing such compositions, and intermediates useful in the preparation of the pyrrolopyrimidine compounds.

BACKGROUND ART

Certain pyrrolopyrimidine compounds are modulators of protein kinases and are therefore useful in protein kinase-mediated diseases, including cancer and chronic inflammation. A particular kinase of interest is epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans). This kinase is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). EGFR is reportedly deregulated in most solid tumor types, such as lung cancer, breast cancer, and brain tumors. Resistance to known therapies develops due to the presence of a mutation of T790M, which is the gatekeeper of EGFR. Certain pyrrolopyrimidine compounds show selective inhibition of the T790M-mutated EGFR inhibitor relative to the wild type EGFR. It is desirable to develop a more efficient EGFR inhibitor that will target substantially the mutated EGFR over the wild type protein. Other protein kinases that are useful targets for small molecule pharmaceuticals include B lymphoid tyrosine kinase (BLK), janus kinase 1 (JAK1), bone marrow kinase on the X chromosome (BMX/ETK), Bruton's tyrosine kinase (BTK), janus kinase 2 (JAK2), janus kinase 3 (JAK3), tyrosine kinase expressed in hepatocellular carcinoma (TEC), resting lymphocyte kinase (TXK, also known as RLK), FMS-like tyrosine kinase 3 (FLT3), and FLT3 (D835Y). Such compounds are described in PCT Publ. No. WO2014/025486.

An efficient method of making such pyrrolopyrimidine kinase inhibitors is needed to allow for clinical testing and commercial use. Such methods, and intermediates useful for the preparation of such compounds, are described herein. Certain salt forms and polymorphs of said compounds are also described.

Certain pyrrolopyrimidine compounds, including N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide and pharmaceutically acceptable salts thereof, are useful in treating tumors and related diseases related to the dysregulation of kinases such as those described herein (including, but not limited to, EGFR (including HER), Alk, and PDGFR pathways). See, e.g., U.S. Pat. No. 8,685,998 B2.

In general, drug stability is an important consideration in the design, manufacture, and storage of pharmaceutical compositions. Drug products that lack stability can form degradation products that can cause undesirable side effects or, in some cases, can cause a decrease in the efficacy and bioavailability of the drug substance itself, making it difficult for physicians to prescribe consistent and effective doses. Therefore, pharmaceutical compositions containing active therapeutic agents, such as those described herein, including N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide and pharmaceutically acceptable salts thereof, that have quick release characteristics, excellent stability, extensive adaptability, and medicinal significance are needed. Described herein are such pharmaceutical compositions.

SUMMARY

The present invention is directed to methods of preparing certain pyrrolopyrimidine derivatives and intermediates useful in their preparation. Also described herein are certain salt forms, polymorphs, and amorphous forms of said compounds.

The present disclosure provides a method of making a compound of Formula

-   wherein -   X¹ is O, NH, or S; -   R¹ and R² are each independently hydrogen, halo, C₁₋₆alkyl, or     C₁₋₆haloalkyl; -   R³ is halo, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy, cyano, or nitro; -   n is 0, 1, 2, 3, or 4; -   R⁴ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, or —NR²²R²³     -   wherein the alkyl and cycloalkyl are unsubstituted or         substituted with hydroxyl or amino; and     -   R²² and R²³ are each independently hydrogen or C₁₋₆alkyl; or R²²         and R²³ taken together with the nitrogen to which they are         attached form a 3- to 10-membered heterocycloalkyl ring; -   R⁵ is hydrogen or C₁₋₆alkyl; -   R⁶ and R⁷ are each independently hydrogen, halo, C₁₋₆alkyl,     C₁₋₆haloalkyl, C₂₋₆alkoxy, C₁₋₆ haloalkoxy, hydroxyl, cyano, or     nitro; -   R⁸ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,     C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; -   R¹¹ and R¹² are each independently hydrogen or C₁₋₆alkyl; -   Q is CR⁹ or N;     -   where R⁹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,         C₁₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; -   —NR¹⁸R¹⁹ is:

-   -   where R¹⁰ is selected from hydrogen and C₁₋₆ alkyl;     -   R¹⁵ is unsubstituted methyl, or is C₂₋₄alkyl unsubstituted or         substituted with hydroxy, methoxy, or halo; and     -   m is 1 or 2; or     -   (b) R¹⁹ and R⁹ are taken together with the atoms to which they         are attached to form a 5- or 6-membered heteroaryl ring         optionally substituted with C₁₋₆alkyl, wherein the alkyl is         unsubstituted or substituted with amino, hydroxyl, halo, or an         N-linked heterocycloalkyl; and R¹⁸ is hydrogen or C₁₋₆alkyl,         where the alkyl is unsubstituted or substituted with amino, or         R¹⁸ is absent to satisfy valency of the heteroaryl ring;         or a pharmaceutically acceptable salt thereof.

The present disclosure is directed to a method of making a compound of Formula (I) or a pharmaceutically acceptable salt thereof, comprising one or more of the following steps:

-   (a) reacting a compound of Formula (X):

-   wherein LG₁ and LG₂ are each a leaving group; and R⁴ and R⁵ are each     as defined for Formula (I); -   with chloromethyl pivalate to form a compound of Formula (XI);

-   (b) reacting a compound of Formula (XI) with a compound of Formula     (XII):

-   wherein X¹, n, and R³ are each as defined for Formula (I); -   to form a compound of Formula (XIII):

-   (c) coupling a compound of Formula (XIII) with a compound of Formula     (XIV):

-   where R⁶, R⁷, R⁸, R¹², R¹⁸, R¹⁹, and Q are each as defined for     Formula (I); to form a compound of Formula (XV):

-   (d) deprotecting the compound of Formula (XV) to form a compound of     Formula (XVI):

-   (e) reducing the compound of Formula (XVI) to form a compound of     Formula (XVII):

-   (f) reacting the compound of Formula (XVII) with acryloyl chloride     to form the compound of Formula (I).

The methods described herein may further comprise the step of reacting a compound of Formula (I) with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt of a compound of Formula (I).

Also contemplated are compounds of Formulae (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII), or salts thereof, which are useful as synthetic intermediates in the described methods.

Also contemplated are pharmaceutically acceptable salt forms of compounds described herein, such as compounds of Formula (I), and polymorphs or amorphous forms of such salts.

Also contemplated are pharmaceutical compositions comprising Compound 1:

(chemical name: N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide) or a pharmaceutically acceptable salt thereof.

In another aspect are described methods of making and methods of manufacturing such pharmaceutical compositions into a dosage form, e.g., a solid oral formulation.

Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an X-ray powder diffractogram of polymorph Form I maleate salt obtained from 1:1 ethanol/H₂O.

FIG. 2 is a differential scanning calorimetry curve of polymorph Form I maleate salt obtained from 1:1 ethanol/H₂O.

FIG. 3 shows a thermogravimetric analysis of polymorph Form I maleate salt obtained from 1:1 ethanol/H₂O.

FIG. 4 is an X-ray powder diffractogram of polymorph Form I maleate salt obtained from 3:7 ethanol/H₂O.

FIG. 5 is an X-ray powder diffractogram of polymorph Form I maleate salt obtained from 1:19 ethanol/H₂O.

FIG. 6 is a differential scanning calorimetry curve of polymorph Form I maleate salt obtained from 1:19 ethanol/H₂O.

FIG. 7 shows a thermogravimetric analysis of polymorph Form I maleate salt obtained from 1:19 ethanol/H₂O.

FIG. 8 is an X-ray powder diffractogram of polymorph Form II maleate salt obtained from ethanol.

FIG. 9 is an X-ray powder diffractogram of polymorph Form II maleate salt obtained from methanol.

FIG. 10 is a differential scanning calorimetry curve of polymorph Form II maleate salt obtained from methanol.

FIG. 11 shows a thermogravimetric analysis of polymorph Form II maleate salt obtained from methanol.

FIG. 12 is an X-ray powder diffractogram of polymorph Form III maleate salt obtained from tetrahydrofuran.

FIG. 13 is a differential scanning calorimetry curve of polymorph Form III maleate salt obtained from tetrahydrofuran.

FIG. 14 shows a thermogravimetric analysis of polymorph Form III maleate salt obtained from tetrahydrofuran.

FIG. 15 is an X-ray powder diffractogram of an amorphous form of the maleate salt obtained from acetone.

FIG. 16 is a differential scanning calorimetry curve of the amorphous form of the maleate salt obtained from acetone.

FIG. 17 shows a thermogravimetric analysis of the amorphous form of the maleate salt obtained from acetone.

FIG. 18 is an X-ray powder diffractogram of the amorphous form of the maleate salt obtained from acetonitrile.

FIG. 19 is a differential scanning calorimetry curve of the amorphous form of the maleate salt obtained from acetonitrile.

FIG. 20 shows a thermogravimetric analysis of the amorphous form of the maleate salt obtained from acetonitrile.

FIG. 21 is an X-ray powder diffractogram of polymorph Form I maleate salt obtained from ethyl acetate.

FIG. 22 is an X-ray powder diffractogram of polymorph Form IV hydrochloride salt obtained from water.

FIG. 23 is a differential scanning calorimetry curve of polymorph Form IV hydrochloride salt obtained from water.

FIG. 24 shows a thermogravimetric analysis of polymorph Form IV hydrochloride salt obtained from water.

FIG. 25 is an X-ray powder diffractogram of polymorph Form IV hydrochloride salt obtained from 3:1 ethanol/water.

FIG. 26 is a differential scanning calorimetry curve of polymorph Form IV hydrochloride salt obtained from 3:1 ethanol/water.

FIG. 27 shows a thermogravimetric analysis of polymorph Form IV hydrochloride salt obtained from 3:1 ethanol/water.

FIG. 28 is an X-ray powder diffractogram of polymorph Form IV hydrochloride salt obtained from 1:1 ethanol/water.

FIG. 29 is a differential scanning calorimetry curve of polymorph Form IV hydrochloride salt obtained from 1:1 ethanol/water.

FIG. 30 shows a thermogravimetric analysis of polymorph Form IV hydrochloride salt obtained from 1:1 ethanol/water.

FIG. 31 is an X-ray powder diffractogram of polymorph Form IV hydrochloride salt obtained from 5:7 ethanol/water.

FIG. 32 is a differential scanning calorimetry curve of polymorph Form IV hydrochloride salt obtained from 5:7 ethanol/water.

FIG. 33 shows a thermogravimetric analysis of polymorph Form IV hydrochloride salt obtained from 5:7 ethanol/water.

FIG. 34 is an X-ray powder diffractogram of polymorph Form IV hydrochloride salt obtained from 3:2 ethanol/water.

FIG. 35 is a differential scanning calorimetry curve of polymorph Form IV hydrochloride salt obtained from 3:2 ethanol/water.

FIG. 36 shows a thermogravimetric analysis of polymorph Form IV hydrochloride salt obtained from 3:2 ethanol/water.

FIG. 37 is an X-ray powder diffractogram of polymorph Form IV hydrochloride salt obtained from 7:3 ethanol/water.

FIG. 38 is a differential scanning calorimetry curve of polymorph Form IV hydrochloride salt obtained from 7:3 ethanol/water.

FIG. 39 shows a thermogravimetric analysis of polymorph Form IV hydrochloride salt obtained from 7:3 ethanol/water.

FIG. 40 is an X-ray powder diffractogram of polymorph Form V fumarate salt obtained from 1:19 ethanol/water.

FIG. 41 is a differential scanning calorimetry curve of polymorph Form V fumarate salt obtained from 1:19 ethanol/water.

FIG. 42 shows a thermogravimetric analysis of polymorph Form V fumarate salt obtained from 1:19 ethanol/water.

FIG. 43 is an X-ray powder diffractogram of polymorph Form VI malate salt obtained from 1:9 ethanol/water.

FIG. 44 is a differential scanning calorimetry curve of polymorph Form VI malate salt obtained from 1:9 ethanol/water.

FIG. 45 shows a thermogravimetric analysis of polymorph Form VI malate salt obtained from 1:9 ethanol/water.

FIG. 46 is an X-ray powder diffractogram of an amorphous form of the sulfate salt obtained from water.

FIG. 47 is a differential scanning calorimetry curve of an amorphous form of the sulfate salt obtained from water.

FIG. 48 shows a thermogravimetric analysis of an amorphous form of the sulfate salt obtained from water.

FIG. 49 is an X-ray powder diffractogram of an amorphous form of the mesylate salt obtained from ethanol/ethyl acetate/water.

FIG. 50 is an X-ray powder diffractogram of an amorphous form of the tosylate salt obtained from water/ethyl acetate.

FIG. 51 is an X-ray powder diffractogram of an amorphous form of the hydrobromide salt obtained from water.

FIG. 52 is a differential scanning calorimetry curve of an amorphous form of the hydrobromide salt obtained from water.

FIG. 53 shows a thermogravimetric analysis of an amorphous form of the hydrobromide salt obtained from water.

FIG. 54 is an X-ray powder diffractogram of polymorph Form VII hydrobromide salt obtained from 1:3 ethanol/water.

DETAILED DESCRIPTION

The present invention is directed to methods of making certain pyrrolopyrimidine derivatives, which are useful in pharmaceutical compositions and in methods of treating proliferation disorders. The compounds as described herein exhibit anti-tumor, anticancer, anti-inflammation, anti-infectious, and anti-proliferation activity. Biological activity of these compounds is described, for example, in PCT Publ. No. WO2014/025486.

Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

The nomenclature used herein to name the subject compounds is illustrated in the Examples herein. This nomenclature has generally been derived using the commercially-available AutoNom software (MDL, San Leandro, Calif.).

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.

Chemical Terms

The term “alkyl” refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

The term “alkoxy” refers to an alkyl group as defined above, bonded to an oxygen atom. The alkoxy group is connected to the parent structure via the oxygen atom.

The term “amino” refers to an —NH₂ group, or a mono- or dialkylamino group.

The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties:

The term “halogen” represents chlorine, fluorine, bromine, or iodine. The term “halo” represents chloro, fluoro, bromo, or iodo. The term “haloalkyl” means an alkyl as defined above, substituted with one or more halogen atoms. The term “haloalkoxy” means an alkoxy as defined above, substituted with one or more halogen atoms.

The term “acyl” refers to a group R—C(O)— where R is from 1 to 10 carbon atoms (C₁₋₁₀) of a straight, branched, or cyclic configuration or a combination thereof, attached to the parent structure through carbonyl functionality. Such R group may be saturated or unsaturated, and aliphatic or aromatic.

The term “cyano” refers to the group —CN.

The term “nitro” refers to the group —NO₂.

The term “hydroxyl” refers to the group —OH.

Those skilled in the art will recognize that the species listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.

Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the embodiments include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically-labelled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of the embodiments and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class of substituents, is meant to refer to embodiments for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C₁₋₃ refers independently to embodiments that have one carbon member (C₁), embodiments that have two carbon members (C₂), and embodiments that have three carbon members (C₃).

Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B—, where A≠B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.

A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates.

For a compound described herein that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. In certain embodiments, the pharmaceutically acceptable salt is the HCl salt, maleic acid salt, HBr salt, hydroxybutanedioic acid salt, fumaric acid salt, lactic acid salt, tartaric acid salt, or methanesulfonic acid salt.

Representative Embodiments Formula (I)

In some embodiments of Formula (I), X¹ is O, NH, or S. In other embodiments, X¹ is O. In other embodiments, X¹ is NH. In other embodiments, X¹ is S.

In some embodiments, R¹ and R² are each independently hydrogen, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl. In certain instances, R¹ is hydrogen. In certain instances, R¹ is C₁₋₆alkyl. In certain instances, R¹ is methyl or ethyl. In certain instances, R² is hydrogen. In certain instances, R² is C₁₋₆alkyl. In certain instances, R² is methyl or ethyl. In certain instances, R¹ and R² are each hydrogen.

In Formula (I), n is 0, 1, 2, 3, or 4. In certain instances, n is zero. In certain instances, n is 1. In certain instances, n is 2. In certain instances, n is 3. In certain instances, n is 4.

In Formula (I), R³ is halo, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy, cyano, or nitro. In certain instances, R³ is halo. In certain instances, R³ is hydroxyl. In certain instances, R³ is C₁₋₆alkyl. In certain instances, R³ is C₁₋₆alkoxy. In certain instances, R³ is cyano. In certain instances, R³ is nitro.

In Formula (I), R⁴ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, or —NR²²R²³; wherein the alkyl and cycloalkyl are unsubstituted or substituted with hydroxyl or amino; and wherein R²² and R²³ are each independently hydrogen or C₁₋₆ alkyl; or R²² and R²³ taken together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl ring. In certain instances, R⁴ is hydrogen. In certain instances, R⁴ is C₁₋₆alkyl. In certain instances, R⁴ is C₃₋₇cycloalkyl. In certain instances, R⁴ is —NR²²R²³.

In certain instances, R⁴ is unsubstituted C₁₋₆alkyl. In certain instances, R⁴ is C₁₋₆ alkyl that is substituted with hydroxyl. In certain instances, R⁴ is C₁₋₃alkyl that is substituted with hydroxyl. In certain instances, R⁴ is C₁₋₆alkyl that is substituted with amino. In certain instances, R⁴ is C₁₋₆alkyl that is substituted with —NH₂. In certain instances, R⁴ is C₁₋₆alkyl that is substituted with —N(CH₃)₂. In certain instances, R⁴ is C₁₋₃alkyl that is substituted with —NH₂. In certain instances, R⁴ is C₁₋₃alkyl that is substituted with —N(CH₃)₂.

In certain instances, R⁴ is unsubstituted C₃₋₇cycloalkyl. In certain instances, R⁴ is unsubstituted C₃cycloalkyl. In certain instances, R⁴ is unsubstituted C₄cycloalkyl. In certain instances, R⁴ is unsubstituted C₅₋₆cycloalkyl. In certain instances, R⁴ is unsubstituted C₇cycloalkyl.

In certain instances, R⁴ is —NR²²R²³, wherein R²² and R²³ are each independently hydrogen or C₁₋₆ alkyl; or R²² and R²³ taken together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl ring. In certain instances, R²² and R²³ are each hydrogen. In certain instances, R²² and R²³ are each C₁₋₆alkyl. In certain instances, R²² and R²³ are each C₁₋₃alkyl. In certain instances, R²² and R²³ are each methyl.

In certain instances, R²² and R²³ are taken together with the nitrogen to which they are attached to form a 3- to 10-membered heterocycloalkyl ring, such that R⁴ is

where w is a number from 1 to 8. In certain instances, R²² and R²³ are taken together with the nitrogen to which they are attached to form a 3-, 4-, 5-, or 6-membered ring.

In Formula (I), R⁵ is hydrogen or C₁₋₆alkyl. In certain instances, R⁵ is hydrogen. In certain instances, R⁵ is C₁₋₆alkyl. In certain instances, R⁵ is methyl. In certain instances, R⁵ is ethyl. In certain instances, R⁵ is C₁₋₃alkyl. In certain instances, R⁵ is C₄₋₆alkyl.

In Formula (I), R⁶ and R⁷ are each independently hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, cyano, or nitro. In certain instances, R⁶ is hydrogen. In certain instances, R⁶ is halo. In certain instances, R⁶ is fluoro. In certain instances, R⁶ is chloro. In certain instances, R⁶ is bromo. In certain instances, R⁶ is C₁₋₆alkyl. In certain instances, R⁶ is C₁₋₆haloalkyl. In certain instances, R⁶ is C₂₋₆alkoxy. In certain instances, R⁶ is C₁₋₆haloalkoxy. In certain instances, R⁶ is hydroxyl. In certain instances, R⁶ is cyano. In certain instances, R⁶ is nitro. In certain instances, R⁷ is hydrogen. In certain instances, R⁷ is halo. In certain instances, R⁷ is fluoro. In certain instances, R⁷ is chloro. In certain instances, R⁷ is bromo. In certain instances, R⁷ is C₁₋₆alkyl. In certain instances, R⁷ is C₁₋₆haloalkyl. In certain instances, R⁷ is C₂₋₆alkoxy. In certain instances, R⁷ is C₁₋₆ haloalkoxy. In certain instances, R⁷ is hydroxyl. In certain instances, R⁷ is cyano. In certain instances, R⁷ is nitro.

In Formula (I), R⁸ is hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, cyano, or nitro. In certain instances, R⁸ is hydrogen. In certain instances, R⁸ is halo. In certain instances, R⁸ is fluoro. In certain instances, R⁸ is chloro. In certain instances, R⁸ is bromo. In certain instances, R⁸ is C₁₋₆alkyl. In certain instances, R⁸ is C₁₋₆haloalkyl. In certain instances, R⁸ is C₁₋₆alkoxy. In certain instances, R⁸ is C₁₋₆ haloalkoxy. In certain instances, R⁸ is hydroxyl. In certain instances, R⁸ is cyano. In certain instances, R⁸ is nitro.

In Formula (I), R¹¹ is selected from hydrogen and C₁₋₆ alkyl. In certain instances, R¹¹ is hydrogen. In certain instances, R¹¹ is C₁₋₆ alkyl. In certain instances, R¹¹ is methyl. In certain instances, R¹¹ is ethyl. In certain instances, R¹¹ is C₁₋₃ alkyl. In certain instances, R¹¹ is C₄₋₆ alkyl.

In Formula (I), R¹² is selected from hydrogen and C₁₋₆ alkyl. In certain instances, R¹² is hydrogen. In certain instances, R¹² is C₁₋₆ alkyl. In certain instances, R¹² is methyl. In certain instances, R¹² is ethyl. In certain instances, R¹² is C₁₋₃ alkyl. In certain instances, R¹² is C₄₋₆ alkyl.

In Formula (I), Q is CR⁹ or N. In certain instances, Q is CR⁹. In certain instances, Q is N.

In Formula (I), R⁹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, hydroxyl, cyano, or nitro. In certain instances, R⁹ is hydrogen. In certain instances, R⁹ is halo. In certain instances, R⁹ is fluoro. In certain instances, R⁹ is chloro. In certain instances, R⁹ is bromo. In certain instances, R⁹ is C₁₋₆alkyl. In certain instances, R⁹ is C₁₋₆haloalkyl. In certain instances, R⁹ is C₁₋₆alkoxy. In certain instances, R⁹ is C₁₋₆ haloalkoxy. In certain instances, R⁹ is hydroxyl. In certain instances, R⁹ is cyano. In certain instances, R⁹ is nitro. In certain instances, R⁹ is hydrogen or fluoro.

In Formula (I), —NR¹⁸R¹⁹ is:

-   -   wherein R¹⁰ is selected from hydrogen and C₁₋₆ alkyl;     -   R¹⁵ is unsubstituted methyl, or is C₂₋₄alkyl unsubstituted or         substituted with hydroxy, methoxy, or halo; and     -   m is 1 or 2; or     -   (b) R¹⁹ and R⁹ are taken together with the atoms to which they         are attached to form a 5- or 6-membered heteroaryl ring         optionally substituted with C₁₋₆alkyl, wherein the alkyl is         unsubstituted or substituted with amino, hydroxyl, halo, or an         N-linked heterocycloalkyl; and R¹⁸ is hydrogen or C₁₋₆alkyl,         where the alkyl is unsubstituted or substituted with amino, or         R¹⁸ is absent to satisfy valency of the heteroaryl ring.

In certain instances, —NR¹⁸R¹⁹ is:

In certain instances, —NR¹⁸R¹⁹ is

In certain instances, —NR¹⁸R¹⁹ is

In Formula (I), R¹⁰ is hydrogen or C₁₋₆alkyl. In certain instances, R¹⁰ is hydrogen. In certain instances, R¹⁰ is C₁₋₆alkyl. In certain instances, R¹⁰ is methyl. In certain instances, R¹⁰ is ethyl. In certain instances, R¹⁰ is C₁₋₃alkyl. In certain instances, R¹⁰ is C₄₋₆ alkyl.

In certain instances, R¹⁵ is methyl, hydroxyethyl, methoxyethyl, or fluoroethyl. In other embodiments, R¹⁵ is fluoroethyl. In some embodiments, m is 1. In other embodiments, m is 2.

In Formula (I), —NR¹⁸R¹⁹ is defined as follows: R¹⁹ and R⁹ are taken together with the atoms to which they are attached to form a 5- or 6-membered heteroaryl ring optionally substituted with C₁₋₆alkyl, wherein the alkyl is unsubstituted or substituted with amino, hydroxyl, halo, or an N-linked heterocycloalkyl, or the alkyl is substituted with amino; and R¹⁸ is hydrogen or C₁₋₆alkyl, where the alkyl is unsubstituted or substituted with amino, or R¹⁸ is absent to satisfy valency of the heteroaryl ring. In some embodiments, the heteroaryl ring is substituted with dimethylaminomethyl or piperidinylmethyl. In other embodiments, R⁹ and R¹⁹ taken together form optionally substituted pyrrole or pyridine. In some instances, R¹⁸ is dimethylaminoethyl.

In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen. In certain instances, R⁶, R⁷, and R⁸ are hydrogen and R⁹ is halo. In certain instances, R⁶, R⁷, and R⁸ are hydrogen and R⁹ is fluoro.

In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen and R¹⁰ is methyl. In certain instances, R⁶, R⁷, R⁸ are hydrogen; R⁹ is halo; and R¹⁰ is methyl. In certain instances, R⁶, R⁷, R⁸ are hydrogen; R⁹ is fluoro; and R¹⁰ is methyl.

In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen and R¹³ is hydrogen. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is halo; and R¹³ is hydrogen. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is fluoro; and R¹³ is hydrogen.

In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen and R¹³ is —CH₂OH. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is halo; and R¹³ is —CH₂OH. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is fluoro; and R¹³ is —CH₂OH.

In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen and R¹³ is —(CH₂)_(m)F, wherein m is a number from one to 3. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is halo; and R¹³ is —(CH₂)_(m)F, wherein m is a number from one to 3. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is fluoro; and R¹³ is —(CH₂)_(m)F, wherein m is a number from one to 3.

Formula (II)

The present disclosure is directed to methods of making a compound of Formula (II):

-   wherein -   R¹ and R² are each independently hydrogen, halo, C₁₋₆alkyl, or     C₁₋₆haloalkyl; -   R⁸ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,     C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; -   Q is CR⁹ or N;     -   where R⁹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,         C₁₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; and -   R¹⁰ is hydrogen or C₁₋₆alkyl; -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (II), R¹ and R² are each hydrogen. In other embodiments, R⁸ is halo, methyl, methoxy, or cyano. In still other embodiments, R⁸ is halo. In still other embodiments, R⁸ is fluoro. In some embodiments, R¹⁰ is methyl, ethyl, or isopropyl. In other embodiments, R¹⁰ is methyl.

Formula (III)

The present disclosure provides methods of making a compound of Formula (III):

-   wherein -   R¹ and R² are each independently hydrogen, halo, C₁₋₆alkyl, or     C₁₋₆haloalkyl; -   R⁸ is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,     hydroxyl, cyano, or nitro; and -   R¹⁰ is C₁₋₆alkyl; -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (III), R¹ and R² are each hydrogen. In other embodiments, R⁸ is halo, methyl, methoxy, or cyano. In still other embodiments, R⁸ is halo. In still other embodiments, R⁸ is fluoro. In some embodiments, R¹⁰ is methyl, ethyl, or isopropyl. In other embodiments, R¹⁰ is methyl.

In some embodiments of compounds of Formula (I), R⁶ and R⁷ may also be methoxy. In other embodiments, R⁶ and R⁷ may also be methoxy, provided that neither R⁶ nor R⁷ is methoxy when R¹⁰ is methyl. In some embodiments, R⁶ is methoxy. In other embodiments, R⁷ is methoxy. In certain instances, R⁷ is hydrogen or methoxy.

In other embodiments of Formula (II) or (III), the

group is replaced with

where m and R¹⁵ are as defined herein.

In certain embodiments, the present disclosure is directed to methods of making a compound selected from the compounds in Table 1, and pharmaceutically acceptable salts thereof.

TABLE 1 Compound Structure Chemical Name 1

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)phenyl)acrylamide 2

N-(3-((2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)phenyl)acrylamide 3

N-(3-((2-((6-(4-mcthylpiperazin-1-yl)pyridin- 3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 4

N-(3-((2-((1-(2-(dimethylamino)ethyl)-1H- indol-5-yl)amino)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)phenyl)acrylamide 5

N-(3((2-((2- ((dimethylamino)methyl)quinolin-6-yl) amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 6

N-(3-((5-cyclopropyl-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 7

N-(3-((5-cyclopropyl-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phcnyl)acrylamidc 8

N-(3-((2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(pyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 9

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 10

N-(3-((5-(2-hydroxyethyl)-2-((4-(4- methylpiperazin-1-yl)phenyl)amino) pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 11

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(2-hydroxyethyl)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 12

N-(3-((5-((dimethylamino)methyl)-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 13

N-(3-((5-((dimethylamino)methyl)-2-((3- fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)phenyl)acrylamide 14

N-(3-((5-(dimethylamino)-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 15

N-(3-((5-(dimethylamino)-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 16

N-(3-((5-(2-(dimethylamino)ethyl)-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 17

N-(3-((5-(2-(dimethylamino)ethyl)-2-((3- fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)phenyl)acrylamide 18

N-(3-((5-(aziridin-1-yl)-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 19

N-(3-((5-(aziridin-1-yl)-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 20

N-(3-((5-(azetidin-1-yl)-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 21

N-(3-((5-(azetidin-1-yl)-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 22

N-(3-((2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(piperidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 23

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(piperidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide 24

N-(3-(2-(4-(1-(2-fluoroethyl)azetidin-3- ylamino)-2-methoxyphenylamino)-7H- pyrrolo[2,3-d]pyrimidin-4- yloxy)phenyl)acrylamide 25

N-(3-(2-(4-(1-(2-fluoroethyl)azetidin-3- ylamino)-2-methoxyphenylamino)-7H- pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide and 26

N-(3-((2-((2-(piperidin-1-ylmethyl)quinolin- 6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phcnyl)acrylamide and pharmaceutically acceptable salts thereof.

Chemical Embodiments

In some embodiments of step (a), LG₁ and LG₂ are each a leaving group. In some embodiments, LG₁ and LG₂ are each independently halo or trifluorosulfonate (triflate). In some embodiments, LG₁ and LG₂ are the same leaving group; in other embodiments, they are different leaving groups. In some embodiments, LG₁ and LG₂ are each halo, or are each Cl, Br, or I, or are each Cl.

In some embodiments, R⁴ and R⁵ are each as defined in any of the various permutations described herein.

In some embodiments of step (a), the reacting is performed in the presence of chloromethyl pivalate and an ionic base such as K₂CO₃, Na₂CO₃, Cs₂CO₃, NaOH, or KOH, or an amine base such as a trialkylamine, for example, Et₃N or iPr₂NEt. In some embodiments, the reacting is performed in the presence of an ionic base. In some embodiments, the ionic base is K₂CO₃. In some embodiments, the solvent for step (a) is a polar solvent such as THF, DMF, or water, or a mixture thereof. In some embodiments, the solvent is a mixture of THF and water.

In some embodiments of step (b), X¹, n, and R³ are each as defined in any of the various permutations described herein. In some embodiments of step (b), the reacting is performed in the presence of an ionic base such as K₂CO₃, Na₂CO₃, Cs₂CO₃, NaOH, or KOH, or an amine base such as a trialkylamine, for example, Et₃N or iPr₂NEt. In some embodiments, the reacting is performed in the presence of an ionic base. In some embodiments, the ionic base is K₂CO₃. In some embodiments, the solvent for step (b) is a polar solvent such as THF, DMF, or water, or a mixture thereof. In some embodiments, the solvent is DMF.

In some embodiments of step (c), R⁶, R⁷, R⁸, R¹², R¹⁸, R¹⁹, and Q are each as defined in any one of the various permutations described herein. In some embodiments, the coupling is a Buchwald-Hartwig cross-coupling reaction or a nucleophilic aromatic substitution. In other embodiments, the coupling is performed in the presence of a palladium catalyst and optionally in the presence of a separate phosphine ligand reagent. In some embodiments, the palladium catalyst is a palladium (0) catalyst. In other embodiments, the palladium catalyst is a palladium (II) catalyst. In other embodiments, the palladium catalyst is Pd₂(dba)₃, Pd(OAc)₂, Pd(PPh₃)₄, PdCl₂(P(o-tolyl)₃)₂, or PdCl₂(PPh₃)₂. In some embodiments, the phosphine ligand is PPh₃, a trialkyl phosphine, dppf, P(o-tolyl)₃, P(t-Bu)₃, BINAP, a dialkylbiarylphosphine, XPhos, XantPhos, or SpanPhos, or the like. In some embodiments, the palladium catalyst is Pd₂(dba)₃. In some embodiments, the coupling is done in the presence of a base such as a hydroxide, carbonate, alkoxide, silylamide, or phosphate base. In some embodiments, the base is K₂CO₃, Cs₂CO₃, NaOtBu, or KOH. In other embodiments, the base is K₂CO₃. In some embodiments of step (c), the coupling is done in a polar solvent, such as t-BuOH, THF, DMF, or water, or a mixture thereof. In other embodiments, the solvent is t-BuOH.

In some embodiments of step (d), the deprotecting is done in the presence of a aqueous hydroxide base in an alcohol solvent. In some embodiments, the hydroxide base is aqueous NaOH or aqueous KOH. In some embodiments, the base is aqueous NaOH, and the solvent is methanol.

In some embodiments of step (e), the reducing step is a catalytic hydrogenation with hydrogen gas (at atmospheric pressure or at above atmospheric pressure) and a palladium, platinum, iron, or nickel catalyst. In some embodiments, the metal catalyst is Pd/C. In some embodiments, the hydrogen gas pressure is about 1 MPa.

In some embodiments, steps (d) and (e) are combined into a single step (d/e), whereby the compound of Formula (XV) is deprotected and reduced in one step to form the compound of Formula (XVII). In this instance, the reaction is performed in the presence of hydrazine hydrate and methanol.

In some embodiments of step (f), the reaction is done in the presence of an amine or ionic base. In some embodiments, the base is an amine base. In other embodiments, the base is iPr₂NEt.

In some embodiments, the compound of Formula (I) is converted to a pharmaceutically acceptable salt by reaction with a pharmaceutically acceptable acid. In some embodiments, the compound of Formula (I) is treated with maleic acid. In other embodiments, the acid is maleic acid, HCl, or HBr.

In some embodiments, the methods described herein are used to make a compound of Formula (II) or a pharmaceutically acceptable salt thereof, or to make a compound of Formula (III) or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of making comprises step (f). In other embodiments, the method comprises steps (e) and (f). In other embodiments, the method comprises steps (d), (e), and (f). In other embodiments, the method comprises steps (c), (d), (e), and (f). In other embodiments, the method comprises steps (b), (c), (d), (e), and (f). In other embodiments, the method comprises steps (a)-(f). In other embodiments, the method comprises step (d/e) in place of steps (d) and (e).

In some embodiments of the compounds of Formula (X) and (XI):

LG₁ and LG₂ are each a leaving group; and R⁴ and R⁵ are each as defined for Formula (I). In some embodiments, LG₁ and LG₂ are each independently halo or trifluorosulfonate (triflate). In some embodiments, LG₁ and LG₂ are the same leaving group; in other embodiments, they are different leaving groups. In some embodiments, LG₁ and LG₂ are each halo, or are each Cl, Br, or I, or are each Cl.

In some embodiments of Formulae (X), (XIII), (XV), (XVI), and (XVII):

R⁴ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, or —NR²²R²³; wherein the alkyl and cycloalkyl are unsubstituted or substituted with hydroxyl or amino; and wherein R²² and R²³ are each independently hydrogen or C₁₋₆ alkyl; or R²² and R²³ taken together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl ring. In certain instances, R⁴ is hydrogen. In certain instances, R⁴ is C₁₋₆alkyl. In certain instances, R⁴ is C₃₋₇cycloalkyl. In certain instances, R⁴ is —NR²²R²³. In certain instances, R⁴ is unsubstituted C₁₋₆alkyl. In certain instances, R⁴ is C₁₋₆alkyl that is substituted with hydroxyl. In certain instances, R⁴ is C₁₋₃alkyl that is substituted with hydroxyl. In certain instances, R⁴ is C₁₋₆alkyl that is substituted with amino. In certain instances, R⁴ is C₁₋₆alkyl that is substituted with —NH₂. In certain instances, R⁴ is C₁₋₆alkyl that is substituted with —N(CH₃)₂. In certain instances, R⁴ is C₁₋₃alkyl that is substituted with —NH₂. In certain instances, R⁴ is C₁₋₃alkyl that is substituted with —N(CH₃)₂. In certain instances, R⁴ is unsubstituted C₃₋₇cycloalkyl. In certain instances, R⁴ is unsubstituted C₃cycloalkyl. In certain instances, R⁴ is unsubstituted C₄cycloalkyl. In certain instances, R⁴ is unsubstituted C₅₋₆cycloalkyl. In certain instances, R⁴ is unsubstituted C₇cycloalkyl. In certain instances, R⁴ is —NR²²R²³, wherein R²² and R²³ are each independently hydrogen or C₁₋₆ alkyl; or R²² and R²³ taken together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl ring. In certain instances, R²² and R²³ are each hydrogen. In certain instances, R²² and R²³ are each C₁₋₆alkyl. In certain instances, R²² and R²³ are each C₁₋₃alkyl. In certain instances, R²² and R²³ are each methyl. In certain instances, R²² and R²³ are taken together with the nitrogen to which they are attached to form a 3- to 10-membered heterocycloalkyl ring, such that R⁴ is

where w is a number from 1 to 8. In certain instances, R²² and R²³ are taken together with the nitrogen to which they are attached to form a 3-, 4-, 5-, or 6-membered ring.

In some embodiments of Formulae (X), (XIII), (XV), (XVI), and (XVII), R⁵ is hydrogen or C₁₋₆alkyl. In certain instances, R⁵ is hydrogen. In certain instances, R⁵ is C₁₋₆ alkyl. In certain instances, R⁵ is methyl. In certain instances, R⁵ is ethyl. In certain instances, R⁵ is C₁₋₃alkyl. In certain instances, R⁵ is C₄₋₆alkyl.

In some embodiments of Formulae (XII), (XIII), (XV), (XVI), and (XVII):

R³ is halo, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy, cyano, or nitro. In certain instances, R³ is halo. In certain instances, R³ is hydroxyl. In certain instances, R³ is C₁₋₆alkyl. In certain instances, R³ is C₁₋₆alkoxy. In certain instances, R³ is cyano. In certain instances, R³ is nitro. In some embodiments, n is 0, 1, 2, 3, or 4. In certain instances, n is zero. In certain instances, n is 1. In certain instances, n is 2. In certain instances, n is 3. In certain instances, n is 4. In certain instances, X¹ is O, NH, or S. In other embodiments, X¹ is O. In other embodiments, X¹ is NH. In other embodiments, X¹ is S.

In some embodiments of Formulae (XIV), (XV), (XVI), and (XVII):

R⁶, R⁷, R⁸, R¹², R¹⁸, R¹⁹, and Q are each as defined for Formula (I);

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), R⁶ and R⁷ are each independently hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, cyano, or nitro. In certain instances, R⁶ is hydrogen. In certain instances, R⁶ is halo. In certain instances, R⁶ is fluoro. In certain instances, R⁶ is chloro. In certain instances, R⁶ is bromo. In certain instances, R⁶ is C₁₋₆alkyl. In certain instances, R⁶ is C₁₋₆haloalkyl. In certain instances, R⁶ is C₂₋₆alkoxy. In certain instances, R⁶ is C₁₋₆haloalkoxy. In certain instances, R⁶ is hydroxyl. In certain instances, R⁶ is cyano. In certain instances, R⁶ is nitro. In certain instances, R⁷ is hydrogen. In certain instances, R⁷ is halo. In certain instances, R⁷ is fluoro. In certain instances, R⁷ is chloro. In certain instances, R⁷ is bromo. In certain instances, R⁷ is C₁₋₆alkyl. In certain instances, R⁷ is C₁₋₆haloalkyl. In certain instances, R⁷ is C₂₋₆alkoxy. In certain instances, R⁷ is C₁₋₆haloalkoxy. In certain instances, R⁷ is hydroxyl. In certain instances, R⁷ is cyano. In certain instances, R⁷ is nitro.

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), R⁸ is hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, cyano, or nitro. In certain instances, R⁸ is hydrogen. In certain instances, R⁸ is halo. In certain instances, R⁸ is fluoro. In certain instances, R⁸ is chloro. In certain instances, R⁸ is bromo. In certain instances, R⁸ is C₁₋₆alkyl. In certain instances, R⁸ is C₁₋₆haloalkyl. In certain instances, R⁸ is C₁₋₆alkoxy. In certain instances, R⁸ is C₁₋₆haloalkoxy. In certain instances, R⁸ is hydroxyl. In certain instances, R⁸ is cyano. In certain instances, R⁸ is nitro.

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), R¹² is hydrogen or C₁₋₆alkyl. In certain instances, R¹² is hydrogen. In certain instances, R¹² is C₁₋₆alkyl. In certain instances, R¹² is methyl. In certain instances, R¹² is ethyl. In certain instances, R¹² is C₁₋₃alkyl. In certain instances, R¹² is C₄₋₆alkyl.

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), Q is CR⁹ or N. In certain instances, Q is CR⁹. In certain instances, Q is N.

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), R⁹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro. In certain instances, R⁹ is hydrogen. In certain instances, R⁹ is halo. In certain instances, R⁹ is fluoro. In certain instances, R⁹ is chloro. In certain instances, R⁹ is bromo. In certain instances, R⁹ is C₁₋₆alkyl. In certain instances, R⁹ is C₁₋₆haloalkyl. In certain instances, R⁹ is C₁₋₆alkoxy. In certain instances, R⁹ is C₁₋₆haloalkoxy. In certain instances, R⁹ is hydroxyl. In certain instances, R⁹ is cyano. In certain instances, R⁹ is nitro. In certain instances, R⁹ is hydrogen or fluoro.

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), —NR¹⁸R¹⁹ is:

-   -   wherein R¹⁰ is selected from hydrogen and C₁₋₆ alkyl;     -   R¹⁵ is unsubstituted methyl, or is C₂₋₄alkyl unsubstituted or         substituted with hydroxy, methoxy, or halo; and     -   m is 1 or 2; or     -   (b) R¹⁹ and R⁹ are taken together with the atoms to which they         are attached to form a 5- or 6-membered heteroaryl ring         optionally substituted with C₁₋₆alkyl, wherein the alkyl is         unsubstituted or substituted with amino, hydroxyl, halo, or an         N-linked heterocycloalkyl; and R⁸ is hydrogen or C₁₋₆alkyl,         where the alkyl is unsubstituted or substituted with amino, or         R⁸ is absent to satisfy valency of the heteroaryl ring.

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), —NR¹⁸R¹⁹ is:

In certain instances, —NR¹⁸R¹⁹ is

In

certain instances, —NR¹⁸R¹⁹ is

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), R¹⁰ is hydrogen or C₁₋₆alkyl. In certain instances, R¹⁰ is hydrogen. In certain instances, R¹⁰ is C₁₋₆alkyl. In certain instances, R¹⁰ is methyl. In certain instances, R¹⁰ is ethyl. In certain instances, R¹⁰ is C₁₋₃alkyl. In certain instances, R¹⁰ is C₄₋₆ alkyl.

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), R¹⁵ is methyl, hydroxyethyl, methoxyethyl, or fluoroethyl. In other embodiments, R¹⁵ is fluoroethyl. In some embodiments, m is 1. In other embodiments, m is 2.

In certain instances of compounds of Formulae (XIV), (XV), (XVI), and (XVII), —NR¹⁸R¹⁹ is defined as follows: R¹⁹ and R⁹ are taken together with the atoms to which they are attached to form a 5- or 6-membered heteroaryl ring optionally substituted with C₁₋₆alkyl, wherein the alkyl is unsubstituted or substituted with amino, hydroxyl, halo, or an N-linked heterocycloalkyl, or the alkyl is substituted with amino; and R¹⁸ is hydrogen or C₁₋₆alkyl, where the alkyl is unsubstituted or substituted with amino, or R¹⁸ is absent to satisfy valency of the heteroaryl ring. In some embodiments, the heteroaryl ring is substituted with dimethylaminomethyl or piperidinylmethyl. In other embodiments, R⁹ and R¹⁹ taken together form optionally substituted pyrrole or pyridine. In some instances, R¹⁸ is dimethylaminoethyl.

In certain instances of the intermediates described herein, R⁶, R⁷, R⁸, and R⁹ are hydrogen. In certain instances, R⁶, R⁷, and R⁸ are hydrogen and R⁹ is halo. In certain instances, R⁶, R⁷, and R⁸ are hydrogen and R⁹ is fluoro. In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen and R¹⁰ is methyl. In certain instances, R⁶, R⁷, R⁸ are hydrogen; R⁹ is halo; and R¹⁰ is methyl. In certain instances, R⁶, R⁷, R⁸ are hydrogen; R⁹ is fluoro; and R¹⁰ is methyl. In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen and R¹³ is hydrogen. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is halo; and R¹³ is hydrogen. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is fluoro; and R¹³ is hydrogen. In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen and R¹³ is —CH₂OH. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is halo; and R¹³ is —CH₂OH. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is fluoro; and R¹³ is —CH₂OH. In certain instances, R⁶, R⁷, R⁸, and R⁹ are hydrogen and R¹³ is —(CH₂)_(m)F, wherein m is a number from one to 3. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is halo; and R¹³ is —(CH₂)_(m)F, wherein m is a number from one to 3. In certain instances, R⁶, R⁷, and R⁸ are hydrogen; R⁹ is fluoro; and R¹³ is —(CH₂)_(m)F, wherein m is a number from one to 3.

The present disclosure is directed to methods of making a compound of Formula (II):

-   wherein -   R¹ and R² are each independently hydrogen, halo, C₁₋₆alkyl, or     C₁₋₆haloalkyl; -   R⁸ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,     C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; -   Q is CR⁹ or N;     -   where R⁹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,         C₁₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; and -   R¹⁰ is hydrogen or C₁₋₆alkyl; -   or a pharmaceutically acceptable salt thereof.

The methods of making compounds of Formula (II) comprise one or more of steps (a)-(f), where R¹, R², R⁸, Q, and R¹⁰ are each defined consistently with Formula (II) or the embodiments of Formula (II) described herein. Said methods further optionally comprise converting a compound of Formula (II) into a pharmaceutically acceptable salt thereof as described herein.

Formula (III)

The present disclosure provides methods of making a compound of Formula (III):

-   wherein -   R¹ and R² are each independently hydrogen, halo, C₁₋₆alkyl, or     C₁₋₆haloalkyl; -   R⁸ is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,     hydroxyl, cyano, or nitro; and -   R¹⁰ is C₁₋₆alkyl; -   or a pharmaceutically acceptable salt thereof.

The methods of making compounds of Formula (III) comprise one or more of steps (a)-(f), where R¹, R², R⁸, Q, and R¹⁰ are each defined consistently with Formula (III) or the embodiments of Formula (III) described herein. Said methods further optionally comprise converting a compound of Formula (III) into a pharmaceutically acceptable salt thereof as described herein.

In some embodiments are methods of making a compound shown in Table 1, or a pharmaceutically acceptable salt thereof.

In some embodiments are methods of making a compound of the following structure:

or a pharmaceutically acceptable salt thereof, using one or more of steps (a)-(f) as described herein.

In certain embodiments, the present disclosure is directed to methods of making N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide:

or a pharmaceutically acceptable salt thereof. In certain embodiments are methods of making the maleate salt of N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide. In certain embodiments are methods of making the hydrochloride salt of N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide. Said methods comprise one or more of the following steps:

-   (a) reacting a compound of Formula (X-1):

-   wherein LG₁ and LG₂ are each a leaving group as defined herein; or     LG₁ and LG₂ are each chloro; -   with chloromethyl pivalate to form a compound of Formula (XI-1);

-   (b) reacting a compound of Formula (XI-1) with a compound of Formula     (XII-1):

-   to form a compound of Formula (XIII-1):

-   (c) coupling a compound of Formula (XIII-1) with a compound of     Formula (XIV-1):

-   to form a compound of Formula (XV-1):

-   (d) deprotecting the compound of Formula (XV-1) to form a compound     of Formula (XVI-1):

-   (e) reducing the compound of Formula (XVI-1) to form a compound of     Formula (XVII-1):

-   (f) reacting the compound of Formula (XVII-1) with acryloyl chloride     to form     N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide.     In some embodiments, reactions are run at a temperature from about     −10° C. to about 100° C.

In other embodiments, the method of making comprises treating N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt. In some embodiments, the acid is maleic acid, HCl, or HBr. In other embodiments, the acid is maleic acid. In other embodiments, the acid is HCl. In some embodiments, the salt thereof is the maleate, HCl, or HBr salt. In other embodiments, the salt thereof is a tosylate, mesylate, fumarate, or malate salt.

The present disclosure also contemplates certain polymorphs or amorphous forms of compounds of Formulae (I), (II), or (III), or pharmaceutically acceptable salts thereof, or of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments are polymorphs or amorphous forms of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the salt is a maleate salt, an HCl salt, an HBr salt, a sulfate salt, a malate salt, a fumarate salt, a mesylate salt, or a tosylate salt. In some embodiments, the pharmaceutically acceptable salts are optionally solvates. In some embodiments is a crystalline polymorph of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the polymorph is Form I (maleate salt), or is Form II (maleate salt), or is Form III (maleate salt), or is Form IV (HCl salt), or is Form V (fumarate salt), or is Form VI (malate salt), or is Form VII (HBr salt), each having the characteristics discussed herein. In some embodiments, the compound is in amorphous form. In some embodiments, the amorphous form is a maleate, sulfate, mesylate, tosylate, or HBr salt of Compound 1.

In some embodiments, the maleate salt of Compound 1 is Form I. In some embodiments, Form I is characterized by an XRPD spectrum comprising one or more peaks at 2θ values (within the error range of the experiment) selected from the group consisting of: 22.14, 21.90, 12.40, 25.52, 26.12, 14.10, 11.60, 26.52, and 17.00. In some embodiments, Form I is characterized by one, two, three, four, five, six, seven, eight, nine, or 10, or more peaks within the error range of those shown in the XRPD spectrum in FIG. 1, or in FIG. 4, or in FIG. 5, or in FIG. 21. The error range may be ±0.2 2θ, ±0.1 2θ, ±0.05 2θ, or another suitable range. In some embodiments, Form I of the maleate salt of Compound 1 is crystallized from ethyl acetate or from an ethanol/water mixture. In some embodiments, Form I is crystallized from ethanol/water. In some embodiments, Form I is crystallized from ethanol/water at a ratio of 1:1 to 1:19 (v/v). In some embodiments, the ethanol/water ratio is 1:1, or is 3:7, or is 1:19.

In some embodiments, the maleate salt of Compound 1 is in crystalline polymorph Form II. In some embodiments Form II is characterized by an XRPD spectrum comprising one or more peaks at 2θ values (within the error range of the experiment) at the positions shown in the XRPD spectrum in FIG. 8 or in FIG. 9. The error range may be ±0.2 2θ, ±0.1 2θ, ±0.05 2θ, or another suitable range. In some embodiments, Form II of the maleate salt of Compound 1 is crystallized from methanol or ethanol.

In some embodiments, the maleate salt of Compound 1 is in crystalline polymorph Form III. In some embodiments Form III is characterized by an XRPD spectrum comprising one or more peaks at 2θ values (within the error range of the experiment) at the positions shown in the XRPD spectrum in FIG. 12. The error range may be ±0.2 2θ, ±0.1 2θ, ±0.05 2θ, or another suitable range. In some embodiments, Form III of the maleate salt of Compound 1 is crystallized from tetrahydrofuran.

In some embodiments, the maleate salt of Compound 1 is in amorphous form. In some embodiments, the amorphous form is prepared by crystallization from acetone or acetonitrile.

In some embodiments, the hydrochloride salt of Compound 1 is crystalline Form IV. In some embodiments, Form IV is characterized by an XRPD spectrum comprising one or more peaks at 2θ values (within the error range of the experiment) at the positions shown in the XRPD spectrum in FIG. 22, or in FIG. 25, or in FIG. 28, or in FIG. 31, or in FIG. 34, or in FIG. 37. The error range may be ±0.2 2θ, ±0.1 2θ, ±0.05 2θ, or another suitable range. In some embodiments, Form IV of the hydrochloride salt of Compound 1 is crystallized from water or from an ethanol/water mixture. In some embodiments, Form IV is crystallized from an ethanol/water mixture in a ration of from 3:1 to 5:7 (v/v). In other embodiments, the ethanol/water ratio is 3:1, 1:1, 5:7, 3:2, or 7:3.

In some embodiments, the fumarate salt of Compound 1 is crystalline Form V. In some embodiments, Form V is characterized by an XRPD spectrum comprising one or more peaks at 2θ values (within the error range of the experiment) at the positions shown in the XRPD spectrum in FIG. 40. The error range may be ±0.2 2θ, ±0.1 2θ, ±0.05 2θ, or another suitable range. In some embodiments, Form V is crystallized from an ethanol/water mixture, optionally 5% aqueous ethanol.

In some embodiments, the malate salt of Compound 1 is crystalline Form VI. In some embodiments, Form VI is characterized by an XRPD spectrum comprising one or more peaks at 2θ values (within the error range of the experiment) at the positions shown in the XRPD spectrum in FIG. 43. The error range may be ±0.2 2θ, ±0.1 2θ, ±0.05 2θ, or another suitable range. In some embodiments, Form VI is crystallized from an ethanol/water mixture, optionally 10% aqueous ethanol.

In some embodiments, the hydrobromide salt of Compound 1 is crystalline Form VII. In some embodiments, Form VII is characterized by an XRPD spectrum comprising one or more peaks at 2θ values (within the error range of the experiment) at the positions shown in the XRPD spectrum in FIG. 54. The error range may be ±0.2 2θ, ±0.1 2θ, ±0.05 2θ, or another suitable range. In some embodiments, Form VII is crystallized from an ethanol/water mixture.

In some embodiments, the pharmaceutically acceptable salt of Compound 1 is in an amorphous form. In some embodiments, the amorphous form is a sulfate salt, optionally prepared by crystallization from water, a mesylate salt, optionally prepared by crystallization from ethanol, a tosylate salt, optionally prepared by crystallization from an ethanol/water mixture, or a hydrobromide salt, optionally prepared by crystallization from water.

Pharmaceutical Compositions

Aside from the pharmacological activity of an active pharmaceutical ingredient (API), there are a variety of physical or physicochemical characteristics of the active substance that are relevant for the preparation of solid oral dosage forms (including oral powders, granules, pellets, tablets, capsules, chewable tablets, dispersible tables, troches or lozenges). To achieve adequate formulation characteristics, such as correct assay, content, and mass uniformity, chemical and physical stability of the drug product, and a proper dissolution rate, the characteristics of the drug product intermediates also have to support a robust manufacturing process.

Therefore, in some aspects, how to achieve suitable adequate formulation characteristics depends on making and manufacturing process for stabilized pharmaceutical compositions containing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or Compound 1, or a pharmaceutically acceptable salt thereof.

While not wishing to be bound by any particular theory, in some instances, the degradation of a compound of Formula (I) or Compound 1 is considered to occur through a pathway involving dimerization of the compound. For example, two molecules of a compound of Formula I could condense under acidic conditions (e.g., during or after salt formation with an acid) to form a dimer. In some embodiments, an amino group on one molecule reacts with the acrylamide group of a second molecule. In some embodiments, the —NR¹⁰ or N—R¹⁵ amino group of one molecule reacts with the acrylamide group in a second molecule to form a β-amino-substituted amido group. In some embodiments, Compound 1 dimerizes. In some embodiments, a dimer of Compound 1 may have the structure Dimer 1 as shown below:

In situations where the compound or salt thereof dimerizes during the formulation process, the dimer may have one or more acid counterions as appropriate for the acid used, e.g., maleate (one molecule, as the dicarboxylate), two bromide counterions, two mesylate counterions, and the like. In some embodiments, the dimer may form as shown below:

Undesired dimerization may be promoted by exposure of the drug substance to heat, air, moisture, stress, compaction, or other interactions or events during the manufacturing process. This dimerization can affect particle size of the drug substance, and thus solubility, stability, and bioavailability of the resulting drug product.

Attempts to reduce dimer-based degradation in active pharmaceutical ingredients (API) have been reported in WO2004/045624 A1 (PCT/JP2003/014504) and Chinese Pat. Publ. No. CN104306348 A (Appln. No. CN20141514067). WO 2004/045624 A1 describes a physical method to control dimer formation for an API by using a coating process, which increases the cost and complexity of the manufacturing process. CN104306348 A describes reducing dimer formation through the addition of various chemical additives (butylated hydroxyanisole, BHA). However, use of such chemicals may be limited due to undesired interactions with other components of the drug product, or regulatory approval considerations.

Therefore, there is a need for stabilized pharmaceutical compositions and the manufacturing process thereof that does not require the addition of restricted chemicals or excipients. There is also a need for manufacturing process for making the stabilized pharmaceutical compositions into suitable pharmaceutical dosage forms, e.g., solid oral formulation, without resorting to a more complex manufacturing process.

In some embodiments are methods of making stabilized pharmaceutical compositions comprising a compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof, comprising pre-blending a suitable adsorbing agent with the therapeutic agent, and then re-blending manufacturing excipients during manufacture of the solid oral formulation, e.g., capsules or tablets. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, it is discovered, surprisingly, that combining a compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof, with a suitable adsorbing agent, prior to formulation into a dosage form, lowers dimerization rate of the compound. While not wishing to be bound by any particular theory, it is considered that the adsorbing agent(s) is able to protect the compound of Formula I or Compound 1, or a pharmaceutically acceptable salt thereof, from physical and environmental stress that, under unprotected conditions, lead to the formation of degradation products such as a dimers, e.g., a dimer having the structure of Dimer 1.

In some embodiments, it is demonstrated that by utilizing one or more suitable adsorbing agent(s) as a blending agent, the formation of degradation products such as a dimer of the compound of Formula I or Compound 1, or a pharmaceutically acceptable salt thereof, e.g., a dimer having the structure of Dimer 1, is significantly reduced. Indeed, it is demonstrated that a dimer of the compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof, e.g., a dimer having the structure of Dimer 1, can be reduced to or maintained at a level that is less than any one of 2.0%, or less than 1.0%, or less than 0.75%, or less than 0.5%, or less than 0.25% of the total weight of the compound of Formula I or Compound 1, or a pharmaceutically acceptable salt thereof, upon completion of formulation, or upon storage for a time point that is at least 3 months, or at least 6 months, or at least 12 months, or at least 18 months, or at least 24 months, or at least 36 months from the date when the pharmaceutical compositions are first formulated. In some embodiments, the dimer or other impurity is detected by HPLC methods known to one of skill in the art.

In some embodiments, the pharmaceutical composition contains from about 0.001% (w/w) to about 1% (w/w) of a dimer of Compound 1, or a pharmaceutically acceptable salt thereof, after a stability test for about 10 days, or about 1 month, or about 2 months, or about 3 months, or about 6 months, or about 12 months, or about 18 months, or about 24 months. In some embodiments, the stability test is conducted at ambient temperature, or at a temperature greater than or equal to about 25° C., or at a temperature of about 25° C., or about 50° C., or about 60° C., or between about 50° C. to about 70° C., and/or under relative humidity conditions of about 50%, or about 60%, or about 70%, or greater than about 70%, and/or under exposure to light, e.g., visible light.

In some embodiments, the pharmaceutical compositions described herein demonstrate improved stability of the compound of Formula I or Compound 1, or a pharmaceutically acceptable salt thereof, (active agent) upon storage or under stability testing conditions relative to substantially the same formulation without the adsorbing agent. In some embodiments, the storage time and stability testing conditions are those described herein.

In some embodiments, the present invention also relates to methods of making the pharmaceutical compositions. Such methods may comprise first pre-blending or re-blending a compound of Formula I or Compound 1, or a pharmaceutically acceptable salt thereof, with a suitable adsorbing agent. The present methods may also comprise first pre-blending a compound of Formula I or Compound 1, or a pharmaceutically acceptable salt thereof, with a suitable adsorbing agent prior to formulation into a dosage form.

An “adsorbing agent” is an inactive pharmaceutical ingredient that performs a minor adsorbing function and that otherwise serves as a binder or filler.

Any suitable adsorbing agent(s) can be used. In particular embodiments, the adsorbing agent is a porous solid powder. In some embodiments, the active ingredient may be adsorbed into the pores of the adsorbing agent. Exemplary adsorbing agents include, but are not limited to, acacia, bentonite, alginic acid, cellulose derivatives, croscarmellose, gelatin, gelatin hydrolysate, mannitol, maltose, fructose, Plasdone, povidone, sodium starch glycolate, sorbitol, sucrose, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, croscarmellose sodium, dicalcium phosphate, carboxymethyl cellulose, hydroxypropyl cellulose, and polyethylene glycol (particularly in spray dried formulations). In certain embodiments, adsorbing agent(s) are suitable excipients to be used in spray drying processes. In certain embodiments, adsorbing agent(s) are silicified microcrystalline celluloses. In some embodiments, the silicified microcrystalline cellulose (SMCC) is Prosolv® SMCC 50, Prosolv® SMCC 50 LD, Prosolv® SMCC 90, Prosolv® SMCC HD 90, or Prosolv® SMCC 90 LM. In other embodiments, the silicified microcrystalline cellulose is Prosolv® SMCC 50 or Prosolv® SMCC 90. In some embodiments, the SMCC is a blend of microcrystalline cellulose and colloidal silicon dioxide. In some embodiments, the SMCC has a particle size range of about 10 to 100 μm, or about 30 to 90 μm, or about 45 to 80 μm. In some embodiments, the SMCC has an average particle size by laser diffraction of about 50 μm, or about 60 μm, or about 65 μm, or about 70 μm. In some embodiments, the SMCC has average particle size by laser diffraction of 125 μm, or has a range of about 70 to about 200 μm, or about 80 to about 180 μm, or about 90 to 160 μm. In some embodiments, the SMCC has a bulk density of between about 0.20 and about 0.50 g/mL, or between about 0.20 and 0.30 g/mL, or between about 0.25 and about 0.37 g/mL, or between about 0.38 and about 0.50 g/mL, or between about 0.27 to about 0.39 g/mL.

In some embodiments, the pharmaceutical composition comprises from about 1% (w/w) to about 90% (w/w), or about 15% (w/w) to about 85% (w/w), or about 35% (w/w) to about 75% (w/w), of the adsorbing agent. In other embodiments, the pharmaceutical composition comprises at least two different kinds of adsorbing agents. In some embodiments, the pharmaceutical composition comprises at least two different kinds of silicified microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises from about 1% (w/w) to about 30% (w/w) of Prosolv® SMCC 50, and from about 30% (w/w) to about 70% (w/w) of Prosolv® SMCC 90.

In some embodiments, the present pharmaceutical compositions may also include pharmaceutically acceptable additive(s) into any suitable type of unit dosage form. Thus, in some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable additive. Suitable additives include, but are not limited to, diluents, binders, vehicles, carriers, excipients, binders, disintegrating agents, lubricants, swelling agents, solubilizing agents, wicking agents, cooling agents, preservatives, stabilizers, sweeteners, flavors, and polymers. While any pharmaceutically acceptable additive is contemplated by the present disclosure, it should be understood that the additives selected for compounding with coated particles of a compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof, should not defeat the stability objectives of the present disclosure. Even though some pharmaceutically acceptable additives may cause degradation of a compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof, such additives may be suitable for the pharmaceutical compositions described herein as long as such additives do not increase dimer formation (relative to the formulation without the further additive) as it is combined with a blending agent, or upon storage, or in vivo.

Examples of disintegrating agents include, but are not limited to, cross-linked sodium carboxymethylcellulose, croscarmellose sodium (e.g., VIVASOL®), crospovidone, and their mixtures. In some embodiments, the pharmaceutical composition comprises from about 0.1% (w/w) to about 10% (w/w), or about 5% (w/w), of croscarmellose sodium (e.g., VIVASOL®).

Examples of lubricating agents include, but are not limited to, magnesium stearate, stearic acid or a pharmaceutically acceptable alkali metal salt thereof, sodium stearyl fumarate, polyethylene glycol (such as Macrogol 6000) (particularly in granule or flake formulations to reduce friction with the mold), glyceryl behenate, talc, colloidal or fumed silicon dioxide and silica derivatives (such as Cab-O-Sil, Syloid® products, and the like), calcium stearate, sodium stearate, sodium lauryl sulfate, sodium chloride, magnesium lauryl sulfate, talc, and their mixtures. A portion of the lubricant may be used as an internal solid lubricant which is blended and granulated with other components of the granulation. Another portion of the lubricant may be added into the final blended material just before compression or encapsulation that coats the outside of the granules in the final formulation. In some embodiments, the pharmaceutical composition further comprises a disintegrating agent and a lubricant. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition comprises from about 0.05% (w/w) to about 5% (w/w) of sodium stearyl fumarate.

Oral pharmaceutical compositions as described herein can generally be in the form of individualized or multi-unit doses, such as tablets, caplets, powders, suspension tablets, chewable tablets, rapid melt tablets, capsules, e.g., a single- or double-shell gelatin capsule, tablet-filled capsules, effervescent powders, effervescent tablets, pellets, granules, liquids, solutions, or suspensions, respectively. In some embodiments, the pharmaceutical composition is formulated as an oral dosage form, or as a solid oral dosage form. In some embodiments, the oral dosage form is an oral powder, a granule, a pellet, a tablet, a capsule, a troch or a lozenge. In some embodiments, the tablet is a chewable tablet, a dispersible tablet, or a troch. In some embodiments, the pharmaceutical composition is formulated to contain a single dose or multiple doses. In some embodiments, each pharmaceutical composition dosage form (e.g., each tablet or capsule) comprises 25 mg, or 50 mg, or 100 mg, or 150 mg, or 200 mg free base equivalent of the compound of Formula I or Compound 1. In some embodiments, the active ingredient (e.g., compound of Formula I or Compound 1 or a pharmaceutically acceptable salt thereof) is present in the pharmaceutical composition at a concentration of about 15 to about 40% (w/w), or about 25 to about 35% (w/w), or about 25% (w/w), or about 30% (w/w), or about 35% (w/w). For salt forms, the concentration is stated as the free base equivalent of the salt form.

Also contemplated are methods of making pharmaceutical compositions with improved stability, bioavailability, and shelf-life. The following exemplary methods of making pharmaceutical compositions in accordance with the presently described processes can be used with any suitable drug. Specifically, the methods described herein are directed to making pharmaceutical compositions comprising any suitable drug that is susceptible to degradation when exposed to the environment or exposed to physical stresses during the manufacturing process.

The pharmaceutical compositions described herein can be made by first combining a drug substance with a suitable adsorbing agent before being processed into capsules or tablets. Combining the drug substance with the adsorbing agent can be accomplished by any suitable methods, e.g., blending, mixing, milling or co-milling, compressing, granulating, dissolving, or precipitating the drug and the adsorbing agent together.

In some embodiments, the combined drug and adsorbing agent are suitable for use in preparing dosage forms by processes including, but not limited to, dry blending, direct compression formulations, and roller compaction formulations.

In some embodiments is a pharmaceutical composition comprising: (a) a compound of Formula (I), or Compound 1:

or a pharmaceutically acceptable salt thereof; and (b) an adsorbing agent that reduces or eliminates formation of a dimer of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction or elimination of dimer formation is upon storage or stability testing, and in other embodiments, the reduction or elimination is in vivo, e.g., after administration of the pharmaceutical composition. In some embodiments, the reduction or elimination is relative to substantially the same formulation, without the adsorbing agent, under the same conditions.

In some embodiments, the pharmaceutical composition comprises Compound 1. In other embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of a maleate salt, a hydrochloride salt, a fumarate salt, a malate salt, a sulfate salt, a mesylate salt, a tosylate salt, and a hydrobromide salt.

In some embodiments, the maleate salt has polymorph Form I. In some embodiments, the maleate salt polymorph Form I is formed by crystallization from an aqueous solution comprising from about 1% (v/v) to about 90% (v/v) of ethanol, or about 100% (v/v) of ethyl acetate. In some embodiments, the maleate salt polymorph Form I is formed by crystallization from an aqueous solution comprising about 50% (v/v) of ethanol. In some embodiments, the maleate salt has polymorph Form II. In some embodiments, the maleate salt polymorph Form II is formed by crystallization from about 100% (v/v) of methanol or ethanol. In some embodiments, the maleate salt has polymorph Form III. In some embodiments, the maleate salt polymorph Form III is formed by crystallization from about 100% (v/v) tetrahydrofuran. In some embodiments, the maleate salt has an amorphous form. In some embodiments, the maleate salt amorphous form is prepared by drying or crystallizing from about 100% (v/v) of acetone or acetonitrile.

In some embodiments, the pharmaceutically acceptable salt of Compound 1 is the hydrochloride salt. In some embodiments, the hydrochloride salt has polymorph Form IV. In some embodiments, the hydrochloride salt polymorph Form IV is formed by crystallization from an aqueous solution comprising from about 0% (v/v) to about 60% (v/v) of ethanol.

In some embodiments, the pharmaceutically acceptable salt of Compound I is the fumarate salt. In some embodiments, the fumarate salt has polymorph Form V. In some embodiments, the fumarate salt polymorph Form V is formed by crystallization from an aqueous solution comprising from about 0% (v/v) to about 60% (v/v) of ethanol.

In some embodiments, the pharmaceutically acceptable salt of Compound I is the malate salt. In some embodiments, the malate salt has polymorph Form VI. In some embodiment, the malate salt polymorph Form VI is formed by crystallization from an aqueous solution comprising from about 0% (v/v) to about 60% (v/v) of ethanol.

In some embodiments, the pharmaceutically acceptable salt of Compound 1 is the sulfate salt, the mesylate salt, the tosylate salt, or the hydrobromide salt. In some embodiments, the sulfate salt, the mesylate salt, the tosylate salt, or the hydrobromide salt is in amorphous form.

In some embodiments, the adsorbing agent reduces the formation of a dimer of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the dimer level in the pharmaceutical composition is below the limits of quantitation of the detection method. In other embodiments, no dimer formation is detected in the pharmaceutical composition.

Also described herein are processes for preparing a pharmaceutical composition as discussed herein, wherein said method comprises: 1) combining a compound of Formula I, or Compound 1, or a pharmaceutically acceptable salt thereof, with an adsorbing agent to form a first mixture; and 2) formulating the first mixture into a dosage form. In some embodiments, the compound or pharmaceutically acceptable salt thereof and the adsorbing agent are combined in a single step to form the first mixture. In some embodiments, the compound or salt and the adsorbing agent are combined in multiple steps to form the first mixture. In some embodiments, the adsorbing agent is a single adsorbing agent. In some embodiments, the adsorbing agent is multiple adsorbing agents. In some embodiments, the multiple adsorbing agents comprise at least two different kinds of silicified microcrystalline cellulose. In some embodiments, the at least two different kinds of silicified microcrystalline cellulose comprise Prosolv® SMCC 50 and Prosolv® SMCC 90. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is combined with multiple different adsorbing agents sequentially, in some cases in one or more blending steps. In some embodiments, the compound or pharmaceutically acceptable salt thereof is combined with Prosolv® SMCC 50 in a first step, and then combined with Prosolv® SMCC 90 in a second step.

In some embodiments, the process further comprises formulating the first mixture into a dosage form in the presence of a pharmaceutically acceptable additive. In some embodiments, the additive comprises a disintegrating agent and/or a lubricant. In some embodiments, the additive comprises a disintegrating agent and a lubricant. In some embodiments, the disintegrating agent is cross-linked sodium carboxymethylcellulose or croscarmellose sodium (e.g., VIVASOL®), and the lubricant is sodium stearyl fumarate.

In some embodiments, the first mixture is formulated into an oral dosage form, e.g., a solid oral dosage form. In some embodiments, the formulating step comprises a dry blend process, a roller compaction process, or a direct compression process. In some embodiments, the dry blend process comprises a pre-blending step to combine the compound of Formula I, or Compound 1, or a pharmaceutically acceptable salt thereof, with a first microcrystalline cellulose, e.g., Prosolv® SMCC 50, to form a pre-mixture, and a re-blending step to combine the pre-mixture and a second microcrystalline cellulose, e.g., Prosolv® SMCC 90, to form the first mixture, and filling the first mixture with a disintegrating agent, e.g., croscarmellose sodium (VIVASOL®) and a lubricant, e.g., sodium stearyl fumarate, into a capsule.

In some embodiments, the roller compaction process comprises a pre-blending roller compaction step to combine Compound 1, or a pharmaceutically acceptable salt thereof, with a first microcrystalline cellulose, e.g., Prosolv® SMCC 50, to form a pre-mixture, and a re-blending step to combine the pre-mixture and a second microcrystalline cellulose, e.g., Prosolv® SMCC 90, to form the first mixture, and filling the first mixture with a disintegrating agent, e.g., croscarmellose sodium (VIVASOL®) and a lubricant, e.g., sodium stearyl fumarate, into a capsule. In some embodiments, the roller compaction process comprises a pre-blending roller compaction step to combine Compound 1, or a pharmaceutically acceptable salt thereof, with a first microcrystalline cellulose, e.g., Prosolv® SMCC 50, to form a pre-mixture, and a re-blending step to combine the pre-mixture and a second microcrystalline cellulose, e.g., Prosolv® SMCC 90, to form the first mixture, and mixing the first mixture with a disintegrating agent, e.g., croscarmellose sodium (VIVASOL®) and a lubricant, e.g., sodium stearyl fumarate, to form a tablet.

In some embodiments, the direct compression process comprises a pre-blending step to combine Compound 1, or a pharmaceutically acceptable salt thereof, with a first microcrystalline cellulose, e.g., Prosolv® SMCC 50, to form a pre-mixture, and a re-blending step to combine the pre-mixture and a second microcrystalline cellulose, e.g., Prosolv® SMCC 90, to form the first mixture, and mixing the first mixture with a disintegrating agent, e.g., croscarmellose sodium (VIVASOL®) and a lubricant, e.g., sodium stearyl fumarate, to form a tablet.

In certain instances, the processes for preparing pharmaceutical compositions further comprise one or more steps as described herein for preparation of a compound of Formula (I) or Compound 1, or of a pharmaceutically acceptable salt thereof. Embodiments are directed to the other processes described herein; and to the product prepared by any of the processes described herein.

EXAMPLES

Exemplary chemical entities, pharmaceutical compositions, and methods of making such compounds and compositions will now be described by reference to the specific examples that follow. Artisans will recognize that, for the chemical syntheses, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the examples below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0° C. to the reflux temperature of the organic solvent used. Some of the reactions described in the examples provided below are run at a temperature from about −10° C. to about 100° C. With respect to the pharmaceutical composition examples, one of ordinary skill in the art will recognize that variations of the examples that follow may be appropriate.

The examples described herein are provided solely to illustrate representative embodiments of the invention. Accordingly, it should be understood, that the invention is not to be limited to the specific conditions or details described in these or any other example discussed herein, and that such examples are not to be construed as limiting the scope of the invention in any way. Throughout the specification, any and all references are specifically incorporated herein by reference in their entireties.

The following abbreviations have been used in the specification and examples: DCM=dichloromethane; DIEA=DIPEA=N,N-diisopropylethylamine; DMF=N,N-dimethylformamide; EtOH=ethanol; EtOAc=ethyl acetate; MeOH=methanol; t-BuOH=tert-butyl alcohol; and THF=tetrahydrofuran.

All solvents and reagents obtained from commercial sources were used without further purification. Both ¹H NMR and ¹³C spectra were performed on a Bruker Avance III 500 MHz spectrometer. The mass spectra (MS) were obtained on a LC-MS PE SCIEX API 150EX using 0.05% HCOOH (aq.)/acetonitrile as the mobile phase.

Compounds of Examples 3-7 were also synthesized as shown in the following scheme:

The following examples are offered to illustrate but not to limit the invention.

Example 1. Synthesis of (2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

To a 500 L reactor was sequentially added 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (31.5 kg), tetrahydrofuran (THF; 280 kg), chloromethyl pivalate (POMCl; 27.5 kg), K₂CO₃ (70 kg), and water (30 kg). The mixture was stirred for 12 h while the reaction temperature was kept between 35±5° C. The reaction mixture was filtered, and the residue was washed with THF until compound 2b was not detected in the filtrate (by thin layer chromatography (TLC)). The filtrate was combined and concentrated under reduced pressure. The residue was then re-dissolved in ethyl acetate (300 kg) and was washed with water until a neutral pH was reached. The organic layer was separated, dried over Na₂SO₄, and concentrated under reduced pressure to afford the title compound, which was used directly for next step without further purification. LC-MS: m/z 302.1 [M+H]⁺.

Example 2. Synthesis of (2-chloro-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

The product of Example 1 was combined with DMF (300 kg), 3-nitrophenol (24 kg), and K₂CO₃ (70 kg). The mixture was stirred for 48 h while the reaction temperature was kept between 35±5° C. The reaction mixture was filtered, and the collected solid was washed with ethyl acetate until no product was detected in the eluting filtrate (by TLC). Approximately one third of the filtrate was diluted with ethyl acetate (180 kg) and water (300 kg). The mixture was stirred for 2 h and the aqueous layer was separated. The upper layer was washed with water (3×300 kg), resulting in a pH neutral solution. The aqueous layers were combined and extracted with ethyl acetate until no product was detected in the aqueous layer by TLC. All the organic layers were combined, dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to a volume of ˜400 L, which was de-colored with activated carbon and then filtered. The filtrate was concentrated under reduced pressure. The residue was re-dissolved in ethyl acetate (25 kg) and petroleum ether (150 kg) and stirred at reflux temperature. The resulting clear solution was allowed to cool to room temperature. The precipitate was collected and dried to afford the title compound. The same procedures were performed on the two remaining portions of the filtrate. The three portions of product were combined and suspended in petroleum ether (300 kg). The suspension was vigorously stirred at reflux for 3 h, and then was allowed to cool to room temperature. The resulting solid was collected and dried to afford the title compound (42.5 kg, 63% over two steps) as a white solid. LC-MS: m/z 405.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.17-8.14 (m, 1H), 8.14-8.13 (m, 1H), 7.63-7.62 (m, 2H), 7.37 (d, J=3.7 Hz, 1H), 6.62 (d, J=3.7 Hz, 1H), 6.18 (s, 2H), 1.17 (s, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 178.4, 161.6, 154.6, 152.7, 152.5, 149.1, 130.3, 128.6, 128.2, 120.8, 117.4, 104.8, 100.3, 65.9, 39.0, 27.0 (*3).

Example 3. Synthesis of (2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

A 500-L, glass-lined reactor was put under an inert atmosphere with nitrogen gas, then was charged with t-butanol (147 kg) under vacuum. Agitation was initiated, and the reactor was heated to 40±5° C. and nitrogen gas was again introduced. To the reactor was added (2-chloro-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (19.10 kg), anhydrous K₂CO₃ (32.02 kg), tris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃; 0.88 kg), dicyclohexyl (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos; 0.90 kg), and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline (9.70 kg). The resulting mixture was heated at 85±5° C. for 6 h. The mixture was cooled to 60±5° C. and then filtered through a pad of diatomaceous earth (4.9 kg) at 50° C. The reactor was washed with ethyl acetate (36 kg). The diatomaceous earth pad was slurried with ethyl acetate for 30 min at 50° C. (two times) and then was filtered.

The above procedure was repeated and the filtrates were all combined to afford 351 kg of ethyl acetate solution (assay amount 50.36 kg of title compound). The ethyl acetate solution was concentrated to dryness. Ethyl acetate (281 kg) was added and the mixture was stirred for 30 min to dissolve the residue. Silica gel (37 kg) was then added and the resulting mixture was stirred for 1 h. The mixture was filtered and the resulting filtrate was charged into a 1000-L glass-lined reactor. The solution was washed with purified water (125 kg×2) and then brine (125 kg). The organic layer was concentrated to dryness at 45±5° C. at a vacuum pressure below ˜0.02 MPa. Ethanol (124 kg) was added to the residue and the resulting mixture was heated at 85±5° C. for 1 h. Heptane (70 kg) was added and the resulting mixture was heated at 85±5° C. and stirred for 1 h. The mixture was cooled to 5±5° C. at a rate of 20° C./h and then was stirred for 5 h. The resulting precipitate was centrifuged. The solid was washed with heptane (20 kg) and dried at 50±5° C. at a pressure below ˜0.02 MPa for 16 h to give the title compound (46.46 kg, 86.4%, 99.21% HPLC purity) as an orange solid. LC-MS: m/z 578.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.17-8.14 (m, 2H), 7.69-7.64 (m, 2H), 7.41 (d, J=15.1 Hz, 1H), 7.13 (d, J=3.7 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.77 (t, J=9.2 Hz, 1H), 6.49 (d, J=3.6 Hz, 1H), 6.10 (s, 2H), 2.97 (s, 4H), 2.59 (s, 4H), 2.32 (s, 3H), 1.14 (s, 9H); ¹³C NMR (125 MHz, CD₃OD) δ 179.32, 163.26, 157.81, 156.67, 155.88, 154.79, 150.34, 138.03 (d, J=10 Hz), 134.50 (d, J=10 Hz), 131.60, 129.92, 126.31, 121.34, 120.12 (d, J=3.75 Hz), 119.02, 115.29, 107.96 (d, J=26.25 Hz), 100.72, 100.39, 67.88, 56.05 (*2), 51.69 (d, J=2.5 Hz, *2), 46.12, 39.84, 27.32 (*3).

Example 3A. Alternative synthesis of (2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

To a 5 L round bottom flask was added t-BuOH (2.5 L), (2-chloro-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (300 g, 0.74 mol), and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline (154 g, 0.74 mol). The reaction mixture was stirred at a speed of 360 rpm for 5-10 min. Potassium carbonate (220 g, 1.59 mol), tris(dibenzylideneacetone)dipalladium (14 g, 0.0153 mol), dicyclohexyl (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (14 g, 0.0294 mol) and another portion of t-BuOH (0.5 L) were then added. The flask was placed in an oil bath (110-120° C.), and the reaction mixture was stirred at reflux under N₂ at the speed of 320 rpm. After stirring for 3-3.5 h, the mixture was allowed to cool to 40-50° C., filtered through diatomaceous earth, and washed with ethyl acetate (300 mL). The combined filtrate was concentrated under reduced pressure to afford the crude product.

The crude material was re-dissolved in ethyl acetate (2.5 L), and silica gel (300 g) was added (for de-colorization). After the mixture was stirred for 15-30 min, the mixture was filtered and washed with ethyl acetate (2 L). The combined filtrate was washed with water (1 L×2) and brine (1 L), and concentrated under reduced pressure to give a second crude product, which was then re-dissolved in hot EtOH (1 L, ˜75° C.) with stirring. The solution was allowed to cool to room temperature. The resulting crystals were collected and washed with n-hexane (200 mL) and dried at 45° C. for 4 h to afford the title compound as a light brown solid (280 g, 96.26% purity by HPLC, 65% yield). mp: 99.5-101.5° C.; [M+H]+: m/z 578.5; ¹H NMR and ¹³C NMR spectral data for (2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate are consistent with those reported in Example 3.

Example 4. Synthesis of N-(3-fluoro-4-(4-methylpiperazin-1-yl) phenyl)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

To a 2000-L glass-lined reactor under vacuum was added methanol (734 kg). Agitation was initiated, and the reactor was charged with (2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (46.46 kg). The reaction mixture was cooled to 10±5° C. and was agitated for 1 h. Aqueous NaOH (2.5 M, 66.4 kg (6.40 kg NaOH dissolved in 60 kg purified water)) was added drop-wise to the reactor over 75 min. The resulting mixture was warmed to 15±5° C. and was stirred for 3 h. The reaction mixture was cooled to 10±5° C. and purified water (372 kg) was added over 60 min. The resulting mixture was stirred at 5±5° C. for 3 h. The resulting precipitate was centrifuged and the cake was washed with purified water (48 kg). The wet cake (88.30 kg) and purified water (372 kg) were stirred for 3 h and then filtered by press filtration, washing with purified water (47 kg). The wet cake (100.80 kg) and ethyl acetate (250 kg) were combined, heated to 75±5° C., and stirred for 1 h. The resulting mixture was allowed to stand for 30 min. The aqueous layer was separated while the top organic layer was cooled to 10±5° C. at a rate of 20° C./h, and was stirred for 10 h. The resulting precipitate was centrifuged to provide 28.6 kg of a first wet cake (98.7% purity by HPLC (1.1% of starting material)). The mother liquor was concentrated at 45±5° C. at a vacuum pressure of below 0.02 MPa to about 55-90 L, heated to 75±5° C., and stirred for 1 h. The solution was cooled to 10±5° C. at a rate of 20° C./h, and was stirred for 5 h. The resulting solid was collected by centrifugation to provide a second wet cake (4.94 kg (95.7% purity by HPLC (2.9% of starting material)). The two wet cake portions of product were combined and dried at 50±5° C. under vacuum at below 0.02 MPa for 16 h to give the title compound (28.38 kg, 76.1%) as a yellow solid. LC-MS: m/z 464.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.77 (s, 1H), 8.22-8.10 (m, 2H), 7.66-7.55 (m, 2H), 7.41 (dd, J=14.8, 2.4 Hz, 1H), 6.96 (s, 1H), 6.88-6.82 (m, 2H), 6.77 (t, J=9.1 Hz, 1H), 6.46 (dd, J=3.5, 1.9 Hz, 1H), 3.05 (s, 4H), 2.63 (s, 4H), 2.37 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 161.93 (s), 156.52 (s), 155.41 (s), 154.92 (s), 154.57 (s), 153.28 (s), 148.87 (s), 135.13 (d, J=11.0 Hz), 134.56 (d, J=9.7 Hz), 130.04 (s), 128.60 (s), 121.10 (s), 120.29 (s), 119.01 (d, J=4.1 Hz), 117.84 (s), 114.57 (s), 107.77 (d, J=25.9 Hz), 99.38 (d, J=4.4 Hz), 55.13 (s, *2), 50.74 (s, *2), 46.05 (s).

Example 4A. Alternative synthesis of N-(3-fluoro-4-(4-methylpiperazin-1-yl) phenyl)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

To a 50-L jacketed reactor heated using hot water (75° C.) were charged (2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1.5 kg, 2.6 mol) and MeOH (30 L). The mixture was heated at reflux until the (2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate was completely dissolved and then was stirred for another 30 min at ˜65° C. At this point, the hot water was removed from jacket, and replaced with cold alcohol (−10˜−15° C.) to cool the reactor. When the temperature inside the reactor reached 10-18° C., a NaOH solution (2.5 M, 2.1 L) was added drop-wise into the reaction over a ˜1 h period. The temperature was kept below 20° C. during the addition. After the addition was completed, the reaction mixture was stirred between 15-20° C. for another ˜5 h. At this point, an in-process HPLC analysis indicated that the (2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate was completely consumed and that there was a partially de-protected intermediate (MW=463.5+30) (less than 10%) in the reaction mixture. The reaction mixture was cooled to 0-5° C., and water (12 L) was added drop-wise into the reactor over 60 min. The temperature was kept below 20° C. during the addition of the water. After the addition of the water, the reaction mixture was stirred for another 15 min. The resulting precipitate (crude product) was collected, washed with water (2 L), and dried under vacuum. The crude material was re-dissolved in ethyl acetate (30 L). The resulting solution was washed with water (10 L×3) and brine (10 L×1). The organic layer was passed through a pad of diatomaceous earth to remove the residual insoluble material. The filtrate was concentrated under reduced pressure at 38-42° C. until the volume of the remaining solution was around 5 L. The remaining solution was allowed to cool to 0-5° C. and was stirred overnight. The precipitate was collected and dried under vacuum to afford the title compound (968 g, 89.98% purity by HPLC, 80% yield) as a light yellow powder. mp: 132.5-134.5° C.; [M+H]+: m/z 464.1; ¹H NMR and ¹³C NMR spectral data for N-(3-fluoro-4-(4-methylpiperazin-1-yl) phenyl)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine are consistent with those reported in Example 4.

Example 5. Synthesis of 4-(3-aminophenoxy)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

A 500-L pressure reactor was pressurized with N₂ to 0.9 MPa for 30 min. The atmosphere in the reactor was exchanged with 0.2 MPa of N₂ (5×). The reactor was charged sequentially with THF (204 kg), N-(3-fluoro-4-(4-methylpiperazin-1-yl) phenyl)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (28.38 kg), and Pd/C (1.42 kg). The reactor atmosphere was exchanged with 0.2 MPa of N₂ (5×), and then pressurized with N₂ to 0.9 MPa for 30 min. The reactor was put under a 0.2 MPa H₂ atmosphere (5×), and then was pressurized with H₂ to ˜0.8-1.0 MPa. The reaction mixture was heated to ˜90-100° C. and stirred under a pressure of ˜0.8-1.0 MPa for 6 h. The reaction mixture was filtrated through a pad of diatomaceous earth (6.0 kg). The reactor and filter cake were washed with ethyl acetate (14 kg+56 kg). The filtrates were combined and concentrated under vacuum (0.02 MPa) at ˜40-50° C. to a residual volume of ˜30-50 L. The solution was diluted with ethyl acetate (226 kg) and was stirred for 30 min. The solution was washed with ˜20% aq. NaCl (141 kg×2). The organic phase was collected and was filtered through a pad of diatomaceous earth (6.0 kg), washing with ethyl acetate (14 kg+56 kg). The filtrates were combined and concentrated under vacuum (0.02 MPa) at ˜40-50° C. to a residual volume of ˜30-50 L. A distill and replace operation was then performed using THF (70 kg×2) to achieve 800 ppm H₂O by KF analysis (<2000 ppm) and Residual of Solvent (ROS) of 4.5% of ethyl acetate (<10.0%) in the residual THF solution with a volume of ˜30-50 L. The solution was diluted with THF (112 kg) and the resulting solution (167 kg, 98.3% purity, 12.9% concentration of title compound by external standard assay, 81.13% assay yield, ˜21.54 kg of title compound) was used directly in the next step. LC-MS: m/z 434.4 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 7.66 (d, J=15.3 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.09 (dd, J=9 Hz, 1.5 Hz, 1H), 6.92 (d, J=3.5 Hz, 1H), 6.83 (t, J=9.2 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.57 (s, 1H), 6.51 (d, J=8.0 Hz, 1H), 6.20 (d, J=3.5 Hz, 1H), 2.99 (s, 4H), 2.58 (s, 4H), 2.31 (s, 3H). ¹³C NMR (125 MHz, CD₃OD) δ 164.18, 158.03, 156.53 (d, J=18 Hz), 156.10, 155.69, 150.64, 138.59 (d, J=11.1 Hz), 134.17 (d, J=9.6 Hz), 130.94, 122.03, 120.31 (d, J=4.1 Hz), 115.12 (d, J=2.8 Hz), 113.42, 112.12, 109.82, 107.831 (d, J=26.3 Hz), 100.32, 100.00, 56.031 (*2), 51.61 (d, J=2.6 Hz, *2), 46.10.

Example 5A. Alternative synthesis of 4-(3-aminophenoxy)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Pd/C (10% on activated carbon, 22.58 g, 0.021 mol), THF (1.8 L) and N-(3-fluoro-4-(4-methylpiperazin-1-yl) phenyl)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (447.77 g, 0.97 mol) were charged into a high-pressure hydrogenation reactor. The air in the reactor was removed by nitrogen flow. Then hydrogen was charged into the reactor to replace the nitrogen (repeated 4 times). Hydrogen pressure was applied at 1 MPa, and temperature was set at 90-100° C. The reaction was agitated for approximately 5 h until no more hydrogen was consumed. The reaction mixture was cooled to room temperature, filtered through a pad of diatomaceous earth to remove the catalyst, and washed with ethyl acetate (0.2 L×3). The combined organic layers were concentrated under reduced pressure at a temperature below 38° C. to afford the crude product. The crude product was re-dissolved in ethyl acetate (5 L) and washed with water (2 L×2). The organic layer was passed through a pad of diatomaceous earth to remove insolubles and washed with ethyl acetate (0.5 L×2). The organic solvent was concentrated under reduced pressure (at a temperature below 38° C.) until the remaining solution was around 1.5 L. The remaining solution was allowed to cool to room temperature. The resulting precipitate was collected and dried under vacuum to afford the title compound (360 g, 97.9% purity by HPLC, 86% yield) as an off-white powder. mp: 213.5-215.5° C.; [M+H]+: m/z 434.4; ¹H NMR and ¹³C NMR spectral data for 4-(3-aminophenoxy)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine are consistent with those reported in Example 5.

Example 6. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide

The solution of 4-(3-aminophenoxy)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine in THF from Example 5 (166 kg (21.4 kg of starting material)) was agitated under vacuum, and then treated with THF (72 kg) and DIEA (10.8 kg). The reaction mixture was cooled to 5±5° C. Acryloyl chloride (6.70 kg) was diluted with THF (18 kg) and was added drop-wise to the mixture at 5+OC over 1.5 h. After 3 h, the reaction mixture was warmed to 10±5° C., and 1 N NaOH (150 kg) was added at 10±5° C. over 2 h. The resulting mixture was then warmed to 20±5° C. and stirred for an additional 3 h. The upper THF layer was separated, and was concentrated under vacuum at 45±5° C. to about 40-60 L. A distillation and replacement operation was then performed using ethyl acetate (55 kg) to obtain a residual ethyl acetate solution (˜40-60 L). The aqueous layer was extracted with ethyl acetate (100 kg). The ethyl acetate layer was combined with the residual ethyl acetate solution, diluted further with ethyl acetate (210 kg), and stirred for 0.5 h. The solution was washed with 20% brine (110 kg×3) and concentrated under vacuum at 45±5° C. to a volume of ˜40-60 L. A distillation and replacement operation was then performed twice using EtOH (44 kg×2) to obtain a residual EtOH solution (˜40-60 L). The resulting solution was diluted with EtOH (88 kg) at 40±5° C., was treated with purified water (154 kg) slowly at 40±5° C. over 2 h, and then was stirred for 2 h. The mixture was cooled to 15±5° C. and was stirred for another 5 h. The resulting precipitate was centrifuged, and the wet cake was washed with 1:1 EtOH/H₂O (22 kg) and then centrifuged again to afford the title compound (22.4 kg) as a pale yellow solid.

The crude material was dissolved in ethyl acetate (75 kg) and EtOH (22 kg), and the resulting solution was added to a silica gel column (88 kg, 200-300 mesh). The title compound was eluted with 4:1 ethyl acetate/EtOH (396 kg/88 kg). Fractions were collected and concentrated under vacuum at 45±5° C. to about 40-50 L. A distill and replace operation was then performed using EtOH (44 kg) to obtain ˜40-60 L of a residual ethanol solution. The solution was diluted with EtOH (107 kg) and was heated to 40±5° C. Purified water (39.6 kg) was added over 1 h, and the resulting mixture was stirred for 2 h. A white solid started to precipitate and the suspension was cooled to 15±5° C. and stirred for 5 h. The mixture was centrifuged and the wet cake was washed with H₂O:EtOH (8.8 kg:13.2 kg). The wet cake was dried under vacuum at 50±5° C. for 16 h to afford the title compound (12.24 kg, 99.39% purity, 50.8% assay yield) as a white solid. LC-MS: m/z 488.6 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 7.69 (t, J=2.0 Hz, 1H), 7.62-7.55 (m, 2H), 7.41 (t, J=8.1 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 7.01-6.99 (m, 2H), 6.80 (t, J=9.2 Hz, 1H), 6.44 (dd, J=17.0, 9.9 Hz, 1H), 6.39-6.32 (m, 2H), 5.77 (dd, J=9.9, 1.9 Hz, 1H), 2.99 (s, 4H), 2.59 (s, 4H), 2.32 (s, 3H). ¹³C NMR (125 MHz, CD₃OD) δ 164.74, 162.50, 156.58, 155.17 (d, J=3.9 Hz), 154.7, 153.6, 139.7, 137.15 (d, J=11.1 Hz), 132.79 (d, J=9.8 Hz), 131.00, 129.41, 126.71, 120.97, 118.79 (d, J=3.9 Hz), 117.52, 116.51, 113.77 (t, J=2.8 Hz), 106.65, 106.44, 98.97, 98.34, 54.64 (*2), 50.36 (d, J=2.5 Hz, *2), 44.72.

Example 6A. Alternative synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide

A reactor (30 L) was charged with 4-(3-aminophenoxy)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (1199 g, 2.77 mol), DIEA (685 g, 5.30 mol) and THF (13 L). When the temperature inside the reactor reached ˜−3° C., a solution of acryloyl chloride (466.5 g, 5.15 mol) in THF (1 L) was added drop-wise into the reactor over a period of 1 h. The temperature was kept between −5-0° C. during the addition. After stirring for another 30 min, a NaOH solution (1 M, 7.5 L) was added slowly to quench the reaction (the temperature kept between −5-0° C.). The final pH value of the solution was around 9-10. The resulting mixture was stirred for another 3-4 h. The upper THF layer was separated and concentrated under reduced pressure at <40° C. The residue was re-dissolved in ethyl acetate (15 L). The lower aqueous layer was extracted with ethyl acetate (5 L). The residue/ethyl acetate solution was combined with the ethyl acetate layers and all were washed with water (5 L×3) and concentrated under reduced pressure to give a crude product (˜1680 g). The crude material was re-dissolved in EtOH (18 L) at 35-40° C. and water (12 L) was added with stirring. The resulting solution was allowed to cool to room temperature and was stirred overnight (16 h). The resulting precipitate was collected and dried under vacuum to afford a second crude product (1010 g). To further purify this crude product (1010 g), silica gel chromatography (4:1 ethyl acetate/EtOH as mobile phase) and two re-crystallizations from EtOH/water (4:1) were performed to yield the title compound (727 g, 99.2% by HPLC, 54% yield) as off-white powder. mp: 122.0-123.5° C.; [M+H]+: m/z 488.6; ¹H NMR and ¹³C NMR spectral data for N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide are consistent with those reported in Example 6.

Example 7. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide maleate di-hydrate

N-(3-(2-(3-Fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (12.20 kg) was added to a reactor containing purified water (180 kg) and ethanol (7.54 kg). The mixture was heated to 40±5° C. A solution of maleic acid (3.14 kg) in purified H₂O (53.1 kg) and EtOH (2.26 kg) was added to the reactor. The resulting mixture was agitated for 1 h at 40±5° C., then was cooled to 25±5° C. at a rate of 20° C./h and was stirred for another 5 h. The resulting precipitate was centrifuged and the cake was washed with the rest of the H₂O/EtOH solution. The wet cake (16.92 kg) was dried for 48 h at 30±5° C. under vacuum to afford the title compound (14.30 kg, 89.3%). LC-MS: m/z 488.6 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.39 (s, 1H), 10.44 (s, 1H), 9.02 (s, 1H), 7.62 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.50 (d, J=15.4 Hz, 1H), 7.42 (t, J=8.2 Hz, 1H), 7.11-7.05 (m, 2H), 6.97 (ddd, J=8.1, 2.3, 0.7 Hz, 1H), 6.82 (t, J=9.4 Hz, 1H), 6.38 (dd, J=16.9, 10.2 Hz, 1H), 6.26 (ddd, J=18.5, 10.2, 1.7 Hz, 2H), 6.14 (s, 2H), 5.76 (dd, J=10.2, 1.5 Hz, 1H), 3.30 (br, 4H), 3.11 (br, 4H), 2.80 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 168.68 (*2), 164.50, 162.36, 156.18, 155.36, 154.97, 154.25, 153.34, 140.30, 137.90 (d, J=11.1 Hz), 136.25 (*2), 131.50, 131.42 (d, J=9.8 Hz), 130.53, 128.52, 122.80, 120.03, 117.70, 116.92, 114.43, 113.47, 106.65 (d, J=26.5 Hz), 98.93 (d, J=23.6 Hz), 53.38 (*2), 48.15 (*2), 42.88.

Example 7A. Alternative synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide maleate di-hydrate

In a 30-L reactor, a combination of several batches of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1481 g, ˜99.2% HPLC purity) was dissolved in EtOH (15 L) at 36° C. Water (2 L) was added drop-wise at this temperature. The mixture was allowed to cool to room temperature and was stirred overnight. The resulting crystals were collected, washed with a small amount of EtOH, and dried under vacuum at 25° C. overnight to afford the free base of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1255 g, 99.61% HPLC purity) as an off-white powder, which was used in the salt formation step.

A reactor (50 L) was charged with 5% EtOH (20 L) at 40° C. The free base of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1255 g, 2.57 mol, 99.61% HPLC purity) was added with stirring. The resulting suspension was stirred vigorously at 40° C. until a slurry was formed. A solution of maleic acid (325 g, 2.8 mol) in 5% EtOH (2 L) was added drop-wise over 15 min. Once the addition was complete, a clear homogeneous solution was obtained. The solution was allowed to cool to room temperature and was stirred overnight. The resulting crystals were collected, washed with 5% EtOH (0.5 L×3), and dried under vacuum at 25° C. for 48 h to afford the title compound as a light-yellow powder (1420 g, 99.67% HPLC purity, 86.4% yield). mp: 171.1-173.2° C.; [M+H]+: m/z 488.6; ¹H NMR and ¹³C NMR spectral data for N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide maleate di-hydrate are consistent with those reported in Example 7.

Additional exemplary compounds not shown in these synthetic examples are prepared from appropriate starting materials using methods analogous to those described in the preceding schemes and examples.

Example 8. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide maleate salt Example 8-1 (Ethanol/Water (1:1))

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1 g, 2.05 mmol) in ethanol (5 mL) at 40° C. was treated with a solution of maleic acid (262 mg, 2.26 mmol) in water (5 mL). The solution was cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (1 g, 76.3% yield) defined as polymorph Form I. Elemental analysis: N: 14.90%; C: 56.54%; H: 5.34%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 1, 2, and 3, respectively.

Example 8-2 (Ethanol/Water (3:7))

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1 g, 2.05 mmol) in ethanol (4.5 mL) and water (8.5 mL) at 40° C. was treated with 1 M aqueous maleic acid (2 mL). The solution was cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (0.9 g, 68.7% yield) defined as polymorph Form I. The XRPD trace for this material is shown in FIG. 4.

Example 8-3 (Ethanol/Water (1:19))

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1255 g, 2.57 mol) in 5% ethanol (20 L) at 40° C. was treated slowly over 15 min with a solution of maleic acid (325 g, 2.8 mol) in 5% ethanol (2 L). The solution was cooled to room temperature and was stirred overnight. The resulting crystals were collected, washed with 5% ethanol (0.5 L×3), and dried under vacuum at 25° C. for 48 h to yield the title compound (1420 g, 86.4% yield) defined as polymorph Form I. Elemental analysis: N: 14.90%; C: 56.54%; H: 5.34%. The XRPD, DSC, and TGA traces for Form I are shown in FIGS. 5, 6, and 7, respectively. Elemental analysis: N: 14.95%; C: 56.54%; H: 5.40%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 5, 6, and 7, respectively.

Example 8-4 (Ethanol)

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1 g, 2.05 mmol) in ethanol (9 mL) at 40° C. was treated with maleic acid (262 mg, 2.26 mmol). The solution was cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (0.8 g, 61.0% yield) defined as polymorph Form II (possible ethanol solvate). Elemental analysis: N: 15.09%; C: 59.08%; H: 5.48%. The XRPD trace for this material is shown in FIG. 8.

Example 8-5 (Methanol)

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1 g, 2.05 mmol) in methanol (9 mL) at 40° C. was treated with maleic acid (262 mg, 2.26 mmol). The solution was cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (0.8 g, 61.0% yield) defined as polymorph Form II (possible methanol solvate). Elemental analysis: N: 14.90%; C: 57.76%; H: 5.37%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 9, 10, and 11, respectively.

Example 8-6 (Tetrahydrofuran)

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1 g, 2.05 mmol) in THF (8 mL) at 40° C. was treated with maleic acid (262 mg, 2.26 mmol). The solution was cooled to room temperature and was stirred overnight. The resulting crystals were collected and dried to yield the title compound (0.7 g, 53.4% yield) defined as polymorph Form III. Elemental analysis: N: 14.64%; C: 59.02%; H: 5.29%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 12, 13, and 14, respectively.

Example 8-7 (Acetone)

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1 g, 2.05 mmol) in acetone (25 mL) at 40° C. was treated with a solution of maleic acid (262 mg, 2.26 mmol) in acetone (5 mL). The solution was cooled to room temperature and was stirred overnight. The mixture was then exposed to air with stirring for 6 h. The resulting crystals were collected and dried to yield the title compound (0.7 g, 53.4% yield) defined as an amorphous form. Elemental analysis: N: 14.97%; C: 58.37%; H: 5.09%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 15, 16, and 17, respectively.

Example 8-8 (Acetonitrile)

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1 g, 2.05 mmol) in acetonitrile (25 mL) at 40° C. was treated with a solution of maleic acid (262 mg, 2.26 mmol) in acetonitrile (5 mL). The solution was cooled to room temperature and was stirred overnight. The resulting crystals were collected and dried to yield the title compound (1 g, 76.3% yield) defined as an amorphous form. Elemental analysis: N: 15.71%; C: 59.03%; H: 5.06%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 18, 19, and 20, respectively.

Example 8-9 (Ethyl Acetate)

A sample of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide maleate salt (0.5 g) was dissolved in ethyl acetate (100 mL) at 40° C. with stirring. The solution was cooled to room temperature and stood overnight without stirring. The resulting crystals were collected and dried to yield the title compound (˜50 mg, 10% yield) defined as polymorph Form I. The XRPD trace for this material is shown in FIG. 21.

Example 9. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide hydrochloride salt Example 9-1 (Water)

To a suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (5 g, 10.3 mmol) in water (25 mL) was added aqueous HCl (1 M, 25 mL, 25 mmol). The mixture was stirred at ˜40-50° C. until it the starting material dissolved. The solution was cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (6 g, 95.2% yield), defined as polymorph Form IV. Elemental analysis: N: 17.49%; C: 57.51%; H: 5.32%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 22, 23, and 24, respectively.

Example 9-2 (Ethanol/Water (3:1))

To the salt obtained in Example 9-1 (1.0 g) was added ethanol (15 mL) and water (5 mL). The resulting suspension was stirred at reflux temperature until it became clear and homogeneous. The solution was then allowed to cool to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (1 g, 100% yield) in a solid form defined as polymorph Form IV. Elemental analysis: N: 17.76%; C: 57.75%; H: 5.37%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 25, 26, and 27, respectively.

Example 9-3 (Ethanol/Water (1:1))

To the above HCl salt as polymorph Form IV (1.0 g) was added 50% aqueous ethanol (10 mL). The resulting suspension was stirred at reflux temperature until it became clear and homogeneous. The solution was then cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (0.61 g, 61% yield) in a solid form defined as polymorph Form IV. Elemental analysis: N: 17.69%; C: 57.87%; H: 5.40%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 28, 29, and 30, respectively.

Example 9-4 (Ethanol/Water (5:7))

To the HCl salt (1.0 g) was added ethanol (7.5 mL) and water (10.5 mL). The resulting suspension was stirred at reflux temperature until it became clear and homogeneous. The solution was then cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (0.6 g, 60% yield) in a solid form defined as polymorph Form IV. Elemental analysis: N: 17.79%; C: 57.92%; H: 5.40%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 31, 32, and 33, respectively.

Example 9-5 (Ethanol/Water (3:2))

To the HCl salt (1.0 g) was added ethanol (6 mL) and water (4 mL). The resulting suspension was stirred at reflux temperature until it became clear and homogeneous. The solution was then cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (0.64 g, 64% yield) in a solid form defined as polymorph Form IV. Elemental analysis: N: 17.66%; C: 57.77%; H: 5.42%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 34, 35, and 36, respectively.

Example 9-6 (Ethanol/Water (7:3))

To the HCl salt (1.0 g) was added 70% aqueous ethanol (20 mL). The resulting suspension was stirred at reflux temperature until it became clear and homogeneous. The solution was then cooled to room temperature with stirring. The resulting crystals were collected and dried to yield the title compound (0.7 g, 70% yield) in a solid form defined as polymorph Form IV. Elemental analysis: N: 17.78%; C: 57.76%; H: 5.40%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 37, 38, and 39, respectively.

Example 10. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide fumarate salt

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (5 g, 10.3 mmol) in 5% aq. ethanol (60 mL) at 40° C. was treated with a solution of fumaric acid (1.5 g, 12.9 mmol) in 5% aq. ethanol (15 mL). Crystals formed, which were collected and dried to yield the title compound (5.4 g, 87.2% yield) defined as polymorph Form V. Elemental analysis: N: 15.31%; C: 57.59%; H: 5.38%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 40, 41, and 42, respectively.

Example 11. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide malate salt

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (2 g, 4.1 mmol) in 10% aq. ethanol (20 mL) at 40° C. was treated with a solution of DL-malic acid (660 mg, 4.93 mmol) in 10% aq. ethanol (5 mL). The solution was cooled to room temperature with stirring. Crystals formed, which were collected and dried to yield the title compound (1.4 g, 55% yield) defined as polymorph Form VI. Elemental analysis: N: 15.17%; C: 57.28%; H: 5.09%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 43, 44, and 45, respectively.

Example 12. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide sulfate salt

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (2 g, 4.1 mmol) in water (10 mL) at room temperature was treated with 1 M H₂SO₄ (5 mL). Crystals formed, which were collected and dried to yield the title compound (1.7 g, 70.8% yield) defined as an amorphous form. Elemental analysis: N: 15.76%; C: 51.15%; H: 5.41%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 46, 47, and 48, respectively.

Example 13. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide mesylate salt

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (1.3 g, 2.67 mmol) in ethanol (10 mL) at 50° C. was treated with methanesulfonic acid (563 mg, 5.86 mmol). The solution was cooled to −10 C without crystal formation. The mixture was concentrated, and the residue dissolved in a mixture of ethanol (5 mL), ethyl acetate (10 mL), and water (0.5 mL), and was stirred at reflux temperature. The solution was cooled to 35° C. and crystals appeared. The resulting crystals were collected and dried to yield the title compound (1.2 g, 66.3% yield) in a solid form defined as amorphous form. The XRPD trace for this material is shown in FIG. 49.

Example 14. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide tosylate salt

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (2.0 g, 4.10 mmol) in ethanol (4 mL) and water (1 mL) at 60° C. was treated with p-toluenesulfonic acid (1.7 g, 9.88 mmol). Ethyl acetate (20 mL) was then added, and the resulting solution was stirred at reflux temperature. The solution was cooled to 0° C. and crystals appeared. The resulting crystals were collected and dried to yield the title compound (2.2 g, 81.5% yield) in a solid form defined as amorphous form. The XRPD trace for this material is shown in FIG. 50.

Example 15. Synthesis of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide hydrobromide salt Example 15-1 (Water)

A stirred suspension of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide (2.0 g, 4.10 mmol) in water (10 mL) at room temperature was treated with 1 M HBr (10 mL). The resulting crystals were collected and dried to yield the title compound (1.8 g, 67.7% yield) in a solid form defined as amorphous form. Elemental analysis: N: 14.92%; C: 48.26%; H: 5.02%. The XRPD, DSC, and TGA traces for this material are shown in FIGS. 51, 52, and 53, respectively.

Example 15-2 (Ethanol/Water (1:3))

The above amorphous HBr salt form (1 g, 2.05 mmol) was dissolved in ethanol (2 mL) at 50° C. with stirring. Water (6 mL) was then added. The solution was cooled to room temperature with stirring overnight. The resulting crystals were collected and dried to yield the title compound (0.7 g, 70% yield) in a solid form defined as polymorph Form VII. The XRPD trace for this material is shown in FIG. 54.

Formulation Example A: Manufacture of Capsules by Dry Blend Process (Rx1)

Capsules containing Compound 1, maleate salt, were prepared by a dry blend process as described below. The final composition of the capsules is shown in Table A1. The flow diagram for the process is shown in Chart A and the process is described in detail below.

TABLE A1 Composition of dry blend capsules (Rx1) Rx1 Quantity Quantity Ingredient (per capsule) (400 capsules) Pre-blending (dry blend) API/API Maleate 25.00 mg/32.80 mg 13.12 g Prosolv ® SMCC 50 22.10 mg 8.84 g Re-blending Prosolv ® SMCC 90 71.85 mg 28.74 g Capsule Preparation Vivasol ® sodium 2.60 mg 1.04 g croscarmellose sodium stearyl fumarate 0.65 mg 0.26 g Capsule weight 130 mg — Batch weight — 52.0 g

Preparation of Composition Rx1.

Crystal Form I of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide, maleate salt (13.12 g; D (v, 0.9)≤19 m) and adsorbing agent Prosolv® SMCC 50 (8.84 g) were mixed in a pre-blending process and the resulting mixture was mixed with Prosolv® SMCC 90 (28.74 g) by a re-blending process to obtain Composition A1. Composition A1, Vivasol® croscarmellose sodium (1.04 g), and sodium stearyl fumarate (0.26 g) were mixed and subjected to final blending to form a final powder, which was then filled into hollow gelatin capsules to prepare Composition Rx1. Characterization data for the final powder are shown in Table A2, and results of dissolution and stability studies for Composition Rx1 are reported in Table A3.

TABLE A2 Final Powder Characteristics Bulk Density 0.30 g/mL Tapped Density 0.50 g/mL Carr's index 34 Angle of repose 34.6°

TABLE A3 Rx1 Characteristics Dissolution (Medium; Method) 99% (Medium, 0.1N HCl; Basket method, 100 rpm) Heat (60° C.-10 days) Dimer Formation 0.01% Humidity (75% RH-10 days) Dimer Formation 0.01% Light (4500 λ ± 500 λ -10 days) Dimer Formation 0.01%

Formulation Example B. Manufacture of Capsules by Roller Compaction Process (Rx2)

Capsules containing Compound 1, maleate salt, were prepared by a roller compaction process. The final composition of the capsules is shown in Table B. The flow diagram for the process is shown in Chart B and the process is described in detail below.

TABLE B1 Composition of roller compaction capsules (Rx2) Rx2 Quantity Quantity Ingredient (per capsule) (1000 capsules) Pre-blending (roller compaction) API/API Maleate 25.00 mg/32.80 mg 32.80 g Prosolv ® SMCC 50 21.90 mg 21.90 g Re-blending Prosolv ® SMCC90 89.30 mg 89.30 g Capsule Preparation Vivasol ® sodium 3.00 mg 3.00 g croscarmellose sodium stearyl fumarate 3.00 mg 3.00 g Capsule weight 150 mg — Batch weight — 150.00 g

Preparation of Composition Rx2.

Crystal Form I of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide, maleate salt (32.80 g; D (v, 0.9)≤37 μm) and adsorbing agent Prosolv® SMCC 50 (21.90 g) were mixed in a pre-blending/roller compaction process and the resulting mixture was mixed with Prosolv® SMCC 90 (89.30 g) by a re-blending process to obtain Composition B1. Composition B1, Vivasol® croscarmellose sodium (3.00 g), and sodium stearyl fumarate (3.00 g) were mixed and subjected to final blending to form a final powder, which was then filled into hollow gelatin capsules to prepare Composition Rx2. Characterization of the final powder is shown in Table B2, and the results of dissolution and stability studies of Composition Rx2 are reported in Table B3.

TABLE B2 Final Powder Characteristics Bulk Density 0.41 g/mL Tapped Density 0.58 g/mL Carr's index 29.3 Angle of repose 43.6°

TABLE B3 Rx2 Characteristics Dissolution (Medium; Method) 96% (Medium, 0.1N HCl; Basket method, 100 rpm) Heat (60° C.-10 days) Dimer Formation 0.21% Humidity (75% RH-10 days) Dimer Formation 0.05% Light (4500 λ ± 500 λ -10 days) Dimer Formation 0.06%

Formulation Example C. Manufacture of Tablets by Direct Compression (Rx3)

Tablets containing Compound 1, maleate salt, were prepared by direct compression. The final composition of the tablets is shown in Table C1. The flow diagram for the process is shown in Chart C and the process is described in detail below.

TABLE C1 Composition of direct compression tables (Rx3) Rx3 Quantity Quantity Ingredient (per tablet) (1000 tablets) Pre-blending API/API Maleate 25.00 mg/32.80 mg 32.80 g Prosolv ® SMCC 50 21.90 mg 21.90 g Re-blending Prosolv ® SMCC 90 89.30 mg 89.30 g Tablet formation Vivasol ® sodium 3.00 mg 3.00 g croscarmellose sodium stearyl fumarate 3.00 mg 3.00 g Capsule weight 150 mg — Batch weight — 150 g

Preparation of Composition Rx3.

Crystal Form I of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide, maleate salt (21.90 g; D (v, 0.9)≤150 μm) and adsorbing agent Prosolv® SMCC 50 (21.90 g) were mixed in a pre-blending process and the resulting mixture was mixed with Prosolv® SMCC 90 (89.30 g) by a re-blending process to obtain Composition C1. Composition C1, Vivasol® croscarmellose sodium (3.00 g), and sodium stearyl fumarate (3.00 g) were mixed and subjected to a final blending to form a final powder, which was then directly pressed into tablets of Composition Rx3. Characterization, of the final powder is shown in Table C2, and results of dissolution and stability studies of Composition Rx3 are reported in Table C3.

TABLE C2 Final Powder Characteristics Bulk Density 0.30 g/mL Tapped Density 0.50 g/mL Carr's index 34 Angle of repose 35.6°

TABLE C3 Composition Rx3 Characteristics Dissolution (Medium; Method) 100% (Medium, 0.1N HCl; Basket method, 100 rpm) Heat (60° C.-10 days) Dimer Formation 0.10% Humidity (75% RH-10 days) Dimer Formation 0.01% Light (4500 λ ± 500 λ -10 days) Dimer Formation 0.01%

Formulation Example D. Manufacture of Tablets by Roller Compaction Process (Rx4)

Tablets containing Compound 1, maleate salt, were prepared by a roller compaction process. The final composition of the tablets is shown in Table D1. The flow diagram for the process is shown in Chart D and the process is described in detail below.

TABLE D1 Composition of roller compaction tablets (Rx4) Rx4 Quantity Quantity Ingredient (per Tablet) (444 Tablets) Pre-blending (roller compaction) API/API Maleate 25.00 mg/32.80 mg 14.58 g Prosolv ® SMCC 50 21.90 mg 9.74 g sodium stearyl fumarate 1.50 mg 0.67 g Re-blending Prosolv ® SMCC 90 89.30 mg 40.2 g Tablet preparation Vivasol ® croscarmellose 3.00 mg 1.4 g sodium sodium stearyl fumarate 1.50 mg 0.7 g Capsule weight 150 mg — Batch weight — 66.70 g

Preparation of Composition Rx4.

Crystal Form I of N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)acrylamide, maleate salt (14.58 g; D (v, 0.9)≤85 μm) and adsorbing agent Prosolv® SMCC 50 (9.74 g) were mixed in a pre-blending/roller compaction process and the resulting mixture was mixed with Prosolv® SMCC 90 (40.2 g) by a re-blending process to obtain Composition D1. Composition D1, Vivasol® croscarmellose sodium (1.4 g), and sodium stearyl fumarate (0.7 g) were mixed and then subjected to a final blending process to form a final powder, which was used to manufacture tablets (Composition Rx4). Characterization of the final powder is shown in Table D2, and results of dissolution and stability studies of Composition Rx4 are reported in Table D3.

TABLE D2 Final Powder Characteristics Bulk Density 0.38 g/mL Tapped Density 0.56 g/mL Carr's index 32.1 Angle of repose 42.2°

TABLE D3 Rx4 Characteristics Dissolution (Medium; Method) 97% (Medium, 0.1N HCl; Basket method, 100 rpm) Heat (60° C.-10 days) Dimer Formation 0.20% Humidity (75% RH-10 days) Dimer Formation 0.05% Light (4500 λ ± 500 λ -10 days) Dimer Formation 0.06%

The pharmaceutical compositions Rx1-Rx4 may be prepared using 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg free base equivalent of the compound of Formula I or Compound 1, and the amounts of the remaining ingredients are adjusted accordingly so they are in the same ratios as in Rx1-Rx4. In other embodiments, the ingredients are the same but the ratios are adjusted as necessary to maintain low dimer formation.

Formulation Example E: Stability Testing

Compositions Rx1-Rx4 were studied in a long-term stability test at 60% (±5%) relative humidity at 25±2° C. for 18 months. Stability testing showed that solid oral formulations manufactured using the methods described herein exhibit limited dimer formation (Table E).

TABLE E Composition Dimer Detected after 18 months Rx1 0.02% Rx2 0.25% Rx3 0.09% Rx4 0.24% 

1. A pharmaceutical composition comprising: (a) a compound of Formula (I):

wherein X¹ is O, NH, or S; R¹ and R² are each independently hydrogen, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl; R³ is halo, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy, cyano, or nitro; n is 0, 1, 2, 3, or 4; R⁴ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, or —NR²²R²³; wherein the alkyl and cycloalkyl are unsubstituted or substituted with hydroxyl or amino; and R²² and R²³ are each independently hydrogen or C₁₋₆alkyl; or R²² and R²³ taken together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl ring; R⁵ is hydrogen or C₁₋₆alkyl; R⁶ and R⁷ are each independently hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; R⁸ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; R¹¹ and R¹² are each independently hydrogen or C₁₋₆alkyl; Q is CR⁹ or N; where R⁹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; —NR¹⁸R¹⁹ is:

where R¹⁰ is selected from hydrogen and C₁₋₆ alkyl; R¹⁵ is unsubstituted methyl, or is C₂₋₄alkyl unsubstituted or substituted with hydroxy, methoxy, or halo; and m is 1 or 2; or (b) R¹⁹ and R⁹ are taken together with the atoms to which they are attached to form a 5- or 6-membered heteroaryl ring optionally substituted with C₁₋₆alkyl, wherein the alkyl is unsubstituted or substituted with amino, hydroxyl, halo, or an N-linked heterocycloalkyl; and R¹⁸ is hydrogen or C₁₋₆alkyl, where the alkyl is unsubstituted or substituted with amino, or R¹⁸ is absent to satisfy valency of the heteroaryl ring; or Compound 1:

or a pharmaceutically acceptable salt of the compound of Formula (I) or Compound 1; and (b) an adsorbing agent that reduces or eliminates formation of a dimer of the compound, or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition contains about 0.001% (w/w) to about 1% (w/w) of the dimer of the compound, or a pharmaceutically acceptable salt thereof, after a stability test for about 10 days to about 24 months.
 2. The pharmaceutical composition of claim 1, which comprises Compound
 1. 3. The pharmaceutical composition of claim 1, which comprises a pharmaceutically acceptable salt of Compound
 1. 4. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable salt of Compound 1 is selected from the group consisting of a maleate salt, a hydrochloride salt, a fumarate salt, a malate salt, a sulfate salt, a mesylate salt, a tosylate salt, and a hydrobromide salt.
 5. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable salt of Compound 1 has a polymorph form selected from Form I, Form II, Form III, Form IV, Form V, and Form VI. 6-19. (canceled)
 20. The pharmaceutical composition of claim 4, wherein the sulfate salt, mesylate salt, tosylate salt, or hydrobromide salt has an amorphous form.
 21. The pharmaceutical composition of claim 1, wherein the adsorbing agent reduces formation a dimer of Compound 1, or a pharmaceutically acceptable salt thereof.
 22. (canceled)
 23. The pharmaceutical composition of claim 1, wherein the adsorbing agent is selected from the group consisting of acacia, alginic acid, croscarmellose, gelatin, gelatin hydrolysate, mannitol, maltose, frustose, Plasdone, povidone, sodium starch glycolate, sorbitol, sucrose, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, croscarmellose sodium, dicalcium phosphate, carboxymethyl cellulose, hydroxypropyl cellulose, and polyethylene gylcol.
 24. The pharmaceutical composition of claim 23, wherein the adsorbing agent comprises Prosolv® SMCC 50, Prosolv® SMCC 50 LD, Prosolv® SMCC 90, Prosolv® SMCC HD 90, or Prosolv® SMCC 90 LM. 25-27. (canceled)
 28. The pharmaceutical composition of claim 24, which comprises Prosolv® SMCC 50 and Prosolv® SMCC
 90. 29. The pharmaceutical composition of claim 28, which comprises from about 1% (w/w) to about 30% (w/w) of Prosolv® SMCC 50, and from about 30% (w/w) to about 70% (w/w) of Prosolv® SMCC
 90. 30. The pharmaceutical composition of claim 1, which further comprises a pharmaceutically acceptable additive selected from the group consisting of a diluent, a binder, a vehicle, a carrier, an excipient, a disintegrating agent, a lubricant, a swelling agent, a solubilizing agent, a wicking agent, a cooling agent, a preservative, a stabilizer, a sweetener, a flavor, and a polymer. 31-32. (canceled)
 33. The pharmaceutical composition of claim 30, wherein the pharmaceutically acceptable additive comprises a disintegrating agent, and the disintegrating agent is cross-linked sodium carb oxymethylcellulose, croscarmellose sodium, crospovidone, or a mixture thereof.
 34. The pharmaceutical composition of claim 33, wherein the lubricant is magnesium stearate, stearic acid and its pharmaceutically acceptable alkali metal salt, sodium stearyl fumarate, Macrogol 6000, glyceryl behenate, colloidal silicon dioxide, calcium stearate, sodium stearate, Cab-O-Sil, Syloid, sodium lauryl sulfate, sodium chloride, magnesium lauryl sulfate, talc, or a mixture thereof.
 35. The pharmaceutical composition of claim 1, which comprises at least two different kinds of adsorbing agents, and further comprises a disintegrating agent and a lubricant. 36-41. (canceled)
 42. The pharmaceutical composition of claim 1, which is formulated for an oral dosage form.
 43. The pharmaceutical composition of claim 42, wherein the oral dosage form is an oral powder, a granule, a pellet, a tablet, a capsule, a troch, or a lozenge.
 44. The pharmaceutical composition of claim 43, wherein the tablet is a chewable tablet, a dispersible tablet, or a troch. 45-47. (canceled)
 48. A process for preparing a pharmaceutical composition of claim 1, comprising: 1) combining Compound 1, or a pharmaceutically acceptable salt thereof, with the adsorbing agent to form a first mixture; and 2) formulating the first mixture into a dosage form. 49-70. (canceled)
 71. A method of preparing a compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of Formula (XVII)

with acryloyl chloride to form the compound of Formula (I);

wherein X¹ is O, NH, or S; R¹ and R² are each independently hydrogen, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl; R³ is halo, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy, cyano, or nitro; n is 0, 1, 2, 3, or 4; R⁴ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, or —NR²²R²³; wherein the alkyl and cycloalkyl are unsubstituted or substituted with hydroxyl or amino; and R²² and R²³ are each independently hydrogen or C₁₋₆alkyl; or R²² and R²³ taken together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl ring; R⁵ is hydrogen or C₁₋₆alkyl; R⁶ and R⁷ are each independently hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; R⁸ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; R¹¹ and R¹² are each independently hydrogen or C₁₋₆alkyl; Q is CR⁹ or N; where R⁹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, hydroxyl, cyano, or nitro; —NR¹⁸R¹⁹ is:

where R¹⁰ is selected from hydrogen and C₁₋₆ alkyl; R¹⁵ is unsubstituted methyl, or is C₂₋₄alkyl unsubstituted or substituted with hydroxy, methoxy, or halo; and m is 1 or 2; or (b) R¹⁹ and R⁹ are taken together with the atoms to which they are attached to form a 5- or 6-membered heteroaryl ring optionally substituted with C₁₋₆alkyl, wherein the alkyl is unsubstituted or substituted with amino, hydroxyl, halo, or an N-linked heterocycloalkyl; and R¹⁸ is hydrogen or C₁₋₆alkyl, where the alkyl is unsubstituted or substituted with amino, or R¹⁸ is absent to satisfy valency of the heteroaryl ring. 72-77. (canceled) 